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Methods in Pharmacology
and Toxicology
Minjun Chen
Yvonne Will Editors
Drug-Induced
Liver Toxicity
Methods in Pharmacology and Toxicology
Series Editor
Y. James Kang
Department of Pharmacology & Toxicology
University of Louisville
Louisville, Kentucky, USA
For further volumes:

http://www.springer.com/series/7653
Drug-Induced Liver Toxicity
Edited by
Minjun Chen
Division of Bioinformatics and Biostatistics, National Center for Toxicological Research,
U.S. Food and Drug Administration, Jefferson, AR, USA
Yvonne Will
Drug Safety Research and Development, Pfizer Inc., Groton, CT, USA
Editors
Minjun Chen Yvonne Will
Division of Bioinformatics and Biostatistics Drug Safety Research and Development
National Center for Toxicological Research Pfizer Inc.
U.S. Food and Drug Administration Groton, CT, USA
Jefferson, AR, USA
ISSN 1557-2153 ISSN 1940-6053 (electronic)

Methods in Pharmacology and Toxicology
ISBN 978-1-4939-7676-8 ISBN 978-1-4939-7677-5 (eBook)
https://doi.org/10.1007/978-1-4939-7677-5
Library of Congress Control Number: 2018930875
© Springer Science+Business Media, LLC, part of Springer Nature 2018, corrected publication 2018
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Foreword
I am honored to have been asked to help introduce this unique monograph on a subject that
has inspired and piqued my clinical and research interest for more than 35 years. Having
been mentored in drug-induced liver injury (DILI) by the late Hyman J Zimmerman for
more than 20 years, I know he would appreciate how far the field has come in expanding the
mechanisms of hepatotoxicity and the clinical signatures of old and new agents causing liver
injury, and would welcome the new regulatory approaches and perspectives of drug develop-
ers that he helped to define before his passing in 1999. While DILI is still infrequently
encountered in clinical practice, its impact on the drug development process and regulatory
actions taken for adverse hepatic effects remains significant. Despite advances in the ability
to define the various forms of hepatotoxicity from hundreds of drugs, weight loss and dietary
supplements, and herbal products, the diagnosis of DILI continues to remain one of exclu-
sion. No specific liver enzyme pattern or histological finding is considered pathognomonic,
as DILI can mimic all forms of acute and chronic liver diseases. As a result, the diagnosis has
come to depend on a constellation of clinically, genetically, and pharmacologically based ele-
ments for which no other cause seems more likely.
Efforts devoted to assigning causality to specific agents suspected to have led to liver
injury have grown considerably over the past 25 years since pioneers in drug hepatotoxicity
established the Roussel-Uclaf Causality Assessment Method (RUCAM), and whose diag-
nostic elements remain the basis upon which most assessments are determined. In the past
10–15 years, numerous global drug registries have been chronicling the clinical and bio-
chemical signatures, outcomes, and prognosis of DILI, and several international consortia
have been convened to help determine potential DILI mechanisms and identify diagnostic
biomarkers. However, without a specific, confirmatory, validated tool to diagnose DILI,
much of our causality assessment process remains circumstantial and dependent on expert
opinion. Even RUCAM, which was developed by expert consensus opinion, remains imper-
fect as a methodology. The US DILI Network method that incorporates an expert opinion
process into the RUCAM elements is considered by many to be the most rigorous causality
method, but can be time consuming, and may still lack complete agreement among its
knowledgeable assessors. Similarly, attempts to identify a “one size fits all” biomarker to
diagnose the innumerable faces of DILI remain incomplete. Moreover, since there are no
specific antidotes to treat acute idiopathic DILI from non-acetaminophen-based drugs,
discontinuation of the suspected agent is generally required. Having to withdraw a drug
that turns out not to be the actual cause of the injury results in several adverse outcomes,
including depriving a patient of a useful treatment for which no good alternatives might
exist, adding erroneous safety information to a drug’s profile, and leading to costly regula-
tory and even medical-legal consequences.
The risks and expenses associated with bringing a new chemical entity to market can be
extremely high, especially since hepatotoxicity is one of the two most common preclinical
toxicities identified and has been responsible for prematurely ending the further develop-
ment of various agents. Although the FDA has not approved any drug since the late 1990s
that has been withdrawn specifically for hepatotoxicity, some agents approved elsewhere
v
vi Foreword
have been shown to be the cause of severe liver injury and numerous compounds have been
abandoned in early phase development in the past two decades due to the risk of DILI. As
a result, DILI stakeholders from all corners of the development globe are turning to various
forms of in silico or in vitro modeling and pharmacoinformatics to help identify which new
chemical entities have a propensity to cause liver injury prior to their expensive entry into
later phase studies.
To help educate drug developers, toxicologists, biochemists, clinicians, and regulators
alike on the diverse aspects and processes involved with identifying DILI, Drs. Minjun
Chen from the FDA’s National Center for Toxicological Research and Yvonne Will from
Pfizer Inc. have brought together the leading scientific and clinical experts in the field of
drug-induced hepatotoxicity to create a timely handbook where all of the latest preclinical
and clinical disciplines converge. Seminal textbooks authored by the late Hyman Zimmerman
and newer compendiums and websites on DILI (such as LiverTox) have provided much of
the clinical information that often aids in identifying the clinical signatures of DILI, and in
understanding its mechanisms of injury, but this current effort emphasizes the newly dis-
covered pharmacologic as well as the most up-to-date clinical and genetic risk factors asso-
ciated with DILI while the search for a diagnostic DILI biomarker continues. Erudite
discussions on the latest mechanisms of DILI, modeling of hepatotoxins, and the structural
alerts that are currently employed to help predict and/or prevent potentially hepatotoxic
compounds from entering further clinical development are among the 30 authoritative
chapters that cover nearly the entire field of hepatotoxicity. The readership of this volume
will benefit from the in-depth reviews on the recent observations derived from the emerg-
ing fields of pharmacogenetics, pharmacoinformatics, proteomics, transcriptomics, among
others applied specifically to DILI, along with discussions on several clinical and preclinical
in vitro and in vivo aspects of liver injury that enhance our understanding of hepatotoxicity.
Chapters devoted to the regulatory science of evaluation and approval of new drugs and
challenges that remain in drug discovery and post-marketing surveillance specifically related
to DILI provide the information that is most helpful to ensure drug safety. In particular,
the chapter by John Senior and Ted Guo of the FDA is one of the most useful summaries
on the history of DILI dating back to the 1950s—providing the necessary clinical and
regulatory context for many of the current efforts in the field of hepatotoxicity.
Specific topics that readers will find most helpful include the latest reviews of the physico-
chemical properties of drugs that form the basis for structural alerts regarding hepatotoxic-
ity. The usefulness of combining the dose of a drug, the degree of its hepatic metabolism,
lipophilicity, and formation of reactive metabolites into the novel “Rule of Two” and other
predictors has offered significant insight into these pharmacologic risk factors. At the pre-
clinical level, the use of various hepatocyte cell lines, the ability to simulate populations at
risk of hepatotoxicity using DILI-sym™, and other novel technologies are proving to be
quite useful in identifying agents that may be hepatotoxic well before the need to expose
such agents to animals or humans. Delving into the development of potentially toxic metab-
olites, assessing the role of BSEP and hepatic transporters, and examining the role of drugs
on mitochondrial toxicity are among other in vitro technologies that are bringing us closer
to a fuller understanding of DILI mechanisms. On the clinical side, the current state of
micro-RNAs and other mechanistic biomarkers to help foretell the severity of acute DILI,
defining the various genetic and other host risk modifiers that help predict who is most likely
to develop DILI, and a review of the regulatory and diagnostic tools at our disposal to best
establish the causality of DILI round out the additional chapters that are included.
Foreword vii
I very much look forward to having this text on my bookshelf as the authoritative
resource on the diverse preclinical, clinical, and regulatory topics that comprise what we
have all come to recognize as a challenging disorder. Drs. Chen and Will are to be con-
gratulated for assembling such an all-star team of hepatotoxicity experts. Their timely and
informative reviews and discussions will no doubt serve the field of drug-induced liver
injury extremely well now and into the foreseeable future.
James H. Lewis
Georgetown University Hospital
Washington, DC, USA
Preface
Drug-induced liver toxicity remains a leading cause of acute liver failure and a major con-
tributor to black box warnings and market withdrawal. Despite tremendous efforts towards
developing new methodologies to better understand, evaluate, and manage liver toxicity,
progress is still limited, and liver toxicity remains a challenging issue for drug developers,
regulators, and clinicians.
Twenty years ago, Dr. Hyman Zimmerman published his monograph, Hepatotoxicity:
The Adverse Effects of Drugs and Other Chemicals on the Liver. In the book, Dr. Zimmerman
postulated the need to develop a database that contained the assessment of hepatotoxic
potential and characteristics of medications. In addition, he suggested that maintaining an
up-to-date list of hepatotoxins would permit the prediction of untested medications by cor-
relating structural features of compounds with hepatotoxic potential.
The strategy Dr. Zimmerman suggested 20 years ago is still valid today. Databases, such
as the LiverTox by the U.S. National Institutes of Health and the Liver Toxicity Knowledge
Base (LTKB) by the U.S. Food and Drug Administration, serve as valuable resources in the
development of new methodologies that aim to assess hepatotoxic risk in humans. New
tools and models have been developed, including “rule-of-two” (Chap. 3), DILI-Sym
(Chap. 6), risk matrix (Chap. 17), and e-DISH (Chap. 20). New technologies are rapidly
advancing, which would help improve assessment and understanding of hepatotoxic poten-
tials of new medications and marketed drugs.
This book provides a comprehensive view of the methodologies for the study of liver
toxicity encountered throughout the whole life cycle of a drug, from drug discovery, to
clinical trial, post-marketing, and even clinical practice. It is organized into six parts. The
first part begins with an introduction to the mechanisms contributing to drug-induced liver
toxicity. The second and third parts introduce in silico and in vitro approaches used to help
mitigate hepatotoxicity liability at the early stages of drug development. The fourth part
describes methodologies applied in regulatory processes, including preclinical studies, clini-
cal trials, and post-marketing surveillance. The fifth part discusses clinical hepatotoxicity.
Emerging technologies are introduced in the final part of the book.
All chapters are written by internationally recognized experts from Big Pharma, regula-
tory agencies, universities, or clinical centers. The in-depth hepatotoxic knowledge pro-
vided in this multiauthor volume will benefit toxicologists, pharmacologists, biochemists,
bioinformaticians, drug discovery and development researchers, clinicians with interest in
liver diseases, and government regulators. Finally, the editors would like to acknowledge all
the authors for their enthusiasm and contributions to this book and the publisher, Springer,
for their ongoing support in this project.
Jefferson, AR, USA Minjun Chen

Groton, CT, USA Yvonne Will
ix
Disclaimer
The opinions expressed by the authors do not reflect the opinions or policies of their
respective institutions. Any statements in this article should not be considered present or
future policy of any regulatory agency.
xi
Contents
Foreword. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v
Preface. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix
Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xvii
Part I Introduction
1 Overview of Mechanisms of Drug-Induced Liver Injury
(DILI) and Key Challenges in DILI Research�� 3
Nabil Noureddin and Neil Kaplowitz
Part II In Silico and Modeling Approaches

2 Detection, Elimination, Mitigation, and Prediction
of Drug-Induced Liver Injury in Drug Discovery�� 21
Francois Pognan
3 Drug-Induced Liver Injury (DILI) Classification
and Its Application on Human DILI Risk Prediction�� 45
Shraddha Thakkar, Minjun Chen, Huixiao Hong, Zhichao Liu,
Hong Fang, and Weida Tong
4 Physicochemical Properties and Structural Alerts�� 61
Lilia Fisk, Nigel Greene, and Russ Naven
5 Quantitative Structure–Activity Relationship Models
for Predicting Risk of Drug-Induced Liver Injury in Humans�� 77
Huixiao Hong, Jieqiang Zhu, Minjun Chen, Ping Gong,
Chaoyang Zhang, and Weida Tong
6 An Introduction to DILIsym® Software, a Mechanistic
Mathematical Representation of Drug-Induced Liver Injury�� 101
Christina Battista, Brett A. Howell, Scott Q. Siler, and Paul B. Watkins
Part III In Vitro Technologies

7 Prediction of Human Liver Toxicity Using In Vitro Assays:
Limitations and Opportunities�� 125
Franck A. Atienzar and Jean-Marie Nicolas
8 Use of Liver-Derived Cell Lines for the Study
of Drug-Induced Liver Injury�� 151
Zhen Ren, Si Chen, Baitang Ning, and Lei Guo
9 Evaluation of Drug-Induced Liver Injuries (DILI)
with Human Hepatocytes: Scientific Rationale
and Experimental Approaches�� 179
Albert P. Li
xiii
xiv Contents
10 Status and Use of Induced Pluripotent Stem Cells (iPSCs)

in Toxicity Testing�� 199
Min Wei Wong, Chris S. Pridgeon, Constanze Schlott,
B. Kevin Park, and Christopher E.P. Goldring
11 Engineered Human Liver Cocultures for Investigating
Drug-Induced Liver Injury�� 213
Chase P. Monckton and Salman R. Khetani
12 Status and Future of 3D Cell Culture in Toxicity Testing�� 249
Monicah A. Otieno, Jinping Gan, and William Proctor
13 Reactive Metabolite Assessment in Drug Discovery
and Development in Support of Safe Drug Design�� 263
Axel Pähler
14 In Vitro Assessment of Mitochondrial Toxicity
to Predict Drug-Induced Liver Injury�� 283
Mathieu Porceddu, Nelly Buron, Pierre Rustin, Bernard Fromenty,
and Annie Borgne-Sanchez
15 Bile Salt Export Pump: Drug-Induced Liver Injury
and Assessment Approaches�� 301
Ruitang Deng
16 High Content Screening for Prediction of Human
Drug-Induced Liver Injury�� 331
Mikael Persson
17 Interpretation, Integration, and Implementation
of In Vitro Assay Data: The Predictive Toxicity Challenge�� 345
Deborah S. Light, Michael D. Aleo, and J. Gerry Kenna
Part IV Methodologies Applied in Regulatory Science

18 Perspectives on the Regulatory and Clinical Science
of Drug-Induced Liver Injury (DILI)�� 367
Mark I. Avigan and Monica A. Muñoz
19 Regulatory Toxicological Studies: Identifying Drug-Induced
Liver Injury Using Nonclinical Studies�� 395
Elizabeth Hausner and Imran Khan
20 Hy’s Law and eDISH for Clinical Studies�� 411
John Senior and Ted Guo
21 Variability in Baseline Liver Test Values in Clinical Trials:
Challenges in Enhancing Drug-Induced Liver Injury Assessment
in Subjects with Liver Disease�� 431
Bereket Tesfaldet, Gyorgy Csako, Tejas Patel, Md Shamsuzzaman,
and Eileen Navarro Almario
22 Postmarketing Surveillance of Drug-Induced Liver Injury�� 459
S. Christopher Jones, Cindy Kortepeter, and Allen D. Brinker
Contents xv
Part V Methodologies for Clinical Studies

23 Host Risk Modifiers in Idiosyncratic Drug-Induced
Liver Injury (DILI) and Its Interplay with Drug Properties�� 477
Camilla Stephens, M. Isabel Lucena, and Raúl J. Andrade
24 Human Leukocyte Antigen (HLA) and Other Genetic
Risk Factors in Drug-Induced Liver Injury (DILI)�� 497
Ann K. Daly
25 Immune Mechanisms in Drug-Induced Liver Injury�� 511
Hartmut Jaeschke and Dean J. Naisbitt
26 Translational and Mechanistic Biomarkers of Drug-Induced
Liver Injury – Candidates and Qualification Strategies �� 533
Daniel J. Antoine
27 Causality Assessment Methods in Drug-Induced Liver Injury�� 555
Rolf Teschke and Gaby Danan
Part VI New Emerging Technologies

28 Circulating MicroRNAs as Novel Biomarkers
of Drug-Induced Liver Injury in Humans�� 597
Julian Krauskopf, Jos C. Kleinjans, and Theo M. de Kok
29 Systems Microscopy Approaches in Unraveling and Predicting
Drug-Induced Liver Injury (DILI)�� 611
Marije Niemeijer, Steven Hiemstra, Steven Wink, Wouter den Hollander,
Bas ter Braak, and Bob van de Water
30 Noninvasive Preclinical and Clinical Imaging of Liver Transporter
Function Relevant to Drug-Induced Liver Injury�� 627
J. Gerry Kenna, John C. Waterton, Andreas Baudy, Aleksandra Galetin,
Catherine D. G. Hines, Paul Hockings, Manishkumar Patel, Daniel Scotcher,
Steven Sourbron, Sabina Ziemian, and Gunnar Schuetz
Erratum to: Regulatory Toxicological Studies: Identifying Drug-Induced
Liver Injury Using Nonclinical Studies�� E1
Index�� 653
Contributors
Michael D. Aleo • Drug Safety Research and Development, Investigative Toxicology,

Pfizer Inc., Groton, CT, USA
Eileen Navarro Almario • Office of Computational Science, Center for Drug Evaluation
and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA
Raúl J. Andrade • Unidad de Gestión de Aparato Digestivo, Servicio de Farmacología
Clínica, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital
Universitario Virgen de la Victoria, Universidad de Málaga, Málaga, Spain
Daniel J. Antoine • MRC Centre for Inflammation Research, The Queen’s Medical
Research Institute, The University of Edinburgh, Edinburgh, UK
Franck A. Atienzar • Non-Clinical Development, Investigative Toxicology Group, UCB
BioPharma SPRL, Braine-l’Alleud, Belgium
Mark I. Avigan • Office of Surveillance and Epidemiology, Center for Drug Evaluation
and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA
Christina Battista • Institute for Drug Safety Sciences, Eshelman School of Pharmacy, The
University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; DILIsym Services,
Inc., Research Triangle Park, NC, USA
Andreas Baudy • Merck & Co., West Point, PA, USA
Annie Borgne-Sanchez • MITOLOGICS Research Lab, Hôpital Robert Debré, Paris,
France; MITOLOGICS SAS, Parc Biocitech, Romainville, France
Bas ter Braak • Division of Toxicology, Leiden Academic Centre for Drug Research,
Leiden University, Leiden, The Netherlands
Allen D. Brinker • Division of Pharmacovigilance, Office of Surveillance and
Epidemiology, Center for Drug Evaluation and Research, U.S. Food and Drug
Administration, Silver Spring, MD, USA
Nelly Buron • MITOLOGICS Research Lab, Hôpital Robert Debré, Paris, France;
MITOLOGICS SAS, Parc Biocitech, Romainville, France
Minjun Chen • Division of Bioinformatics and Biostatistics, National Center for
Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, USA
Si Chen • Division of Biochemical Toxicology, National Center for Toxicological Research,
U.S. Food and Drug Administration, Jefferson, AR, USA
Gyorgy Csako • National Heart, Lung, and Blood Institute, National Institutes of
Health, Bethesda, MD, USA
Ann K. Daly • Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne,
UK
Gaby Danan • Pharmacovigilance Consultancy, Paris, France
Ruitang Deng • Department of Biomedical and Pharmaceutical Sciences, College of
Pharmacy, University of Rhode Island, Kingston, RI, USA
Hong Fang • Office of Scientific Coordination, National Center for Toxicological
Research, U.S. Food and Drug Administration, Jefferson, AR, USA
Lilia Fisk • Lhasa Limited, Leeds, UK
xvii
xviii Contributors
Bernard Fromenty • INSERM, INRA, Univ Rennes 1, Univ Bretagne Loire, Nutrition,

Metabolism and Cancer (NuMeCan), Rennes, France
Aleksandra Galetin • University of Manchester, Manchester, UK
Jinping Gan • Metabolism and Pharmacokinetics, Bristol-Myers Squibb, Princeton, NJ, USA
Christopher E.P. Goldring • Department of Molecular and Clinical Pharmacology,
MRC Centre for Drug Safety Science, University of Liverpool, Liverpool, UK
Ping Gong • Environmental Laboratory, U.S. Army Engineer Research and Development
Center, Vicksburg, MS, USA
Nigel Greene • Astra Zeneca, Waltham, MA, USA
Lei Guo • Division of Biochemical Toxicology, National Center for Toxicological,
Ted Guo • Office of Biostatistics, Office of Translational Sciences, Center for Drug
Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD,
USA
Elizabeth Hausner • Division of Cardiovascular and Renal Products, Center for Drug
Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA
Steven Hiemstra • Division of Toxicology, Leiden Academic Centre for Drug Research,
Catherine D.G. Hines • Merck & Co., West Point, PA, USA
Paul Hockings • Antaros Medical, BioVenture Hub, Mölndal, Sweden; MedTech West,
Chalmers University of Technology, Gothenburg, Sweden
Wouter den Hollander • Division of Toxicology, Leiden Academic Centre for Drug
Research, Leiden University, Leiden, The Netherlands
Huixiao Hong • Division of Bioinformatics and Biostatistics, National Center for
Brett A. Howell • DILIsym Services, Inc., Research Triangle Park, NC, USA
Hartmut Jaeschke • Department of Pharmacology, Toxicology and Therapeutics,
University of Kansas Medical Center, Kansas City, KS, USA
S. Christopher Jones • Division of Pharmacovigilance, Office of Surveillance and
Epidemiology, Center for Drug Evaluation and Research, U.S. Food and Drug
Administration, Silver Spring, MD, USA
Neil Kaplowitz • USC Research Center for Liver Disease, Keck School of Medicine,
University of Southern California, Los Angeles, CA, USA
J. Gerry Kenna • Bioxydyn, Manchester Science Park, Manchester, UK; Safer Medicines
Trust, Kingsbridge, UK
Imran Khan • Division of Anesthesia, Analgesia and Addiction Products, Center for Drug
Salman R. Khetani • Department of Bioengineering, University of Illinois at Chicago,
Chicago, IL, USA
Jos C. Kleinjans • Department of Toxicogenomics, Maastricht University, Maastricht,
The Netherlands
Theo M. de Kok • Department of Toxicogenomics, Maastricht University, Maastricht,
The Netherlands
Cindy Kortepeter • Division of Pharmacovigilance, Office of Surveillance and Epidemiology,
Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver
Spring, MD, USA
Contributors xix
Julian Krauskopf • Department of Toxicogenomics, Maastricht University, Maastricht,

The Netherlands; Department of Toxicogenomics, GROW School for Oncology and
Developmental Biology, Maastricht University, Maastricht, The Netherlands
Albert P. Li • In Vitro ADMET Laboratories Inc., Columbia, MD, USA
Deborah S. Light • Drug Safety Research and Development, Investigative Toxicology,
Pfizer Inc., Groton, CT, USA
Zhichao Liu • Division of Bioinformatics and Biostatistics, National Center for
M. Isabel Lucena • Unidad de Gestión de Aparato Digestivo, Servicio de Farmacología
Chase P. Monckton • Department of Bioengineering, University of Illinois at Chicago,
Chicago, IL, USA
Monica A. Muñoz • Office of Surveillance and Epidemiology, Center for Drug
Dean J. Naisbitt • Department of Molecular and Clinical Pharmacology, MRC Centre
for Drug Safety Science, University of Liverpool, Liverpool, UK
Russ Naven • Takeda International, Cambridge, MA, USA
Jean-Marie Nicolas • Non-Clinical Development, Development DMPK/PKPD, UCB
BioPharma SPRL, Braine-l'Alleud, Belgium
Marije Niemeijer • Division of Toxicology, Leiden Academic Centre for Drug Research,
Baitang Ning • Division of Systems Biology, National Center for Toxicological,
Nabil Noureddin • USC Research Center for Liver Disease, Keck School of Medicine,
University of Southern California, Los Angeles, CA, USA
Monicah A. Otieno • Preclinical Development & Safety, Janssen Pharmaceuticals,
Spring House, PA, USA
Axel Pähler • Pharmaceutical Sciences, Roche Pharmaceutical Research and Early
Development, pRED, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel,
Switzerland
B. Kevin Park • Department of Molecular and Clinical Pharmacology, MRC Centre for
Drug Safety Science, University of Liverpool, Liverpool, UK
Manishkumar Patel • Merck & Co., West Point, PA, USA
Tejas Patel • Office of Computational Science, Center for Drug Evaluation and Research,
U.S. Food and Drug Administration, Silver Spring, MD, USA
Mikael Persson • Drug Safety and Metabolism, Innovative Medicines and Early
Development, AstraZeneca R&D Gothenburg, Mölndal, Sweden
Francois Pognan • Discovery Investigative Safety, PreClinical Safety, Novartis
Pharmaceutical AG, Basel, Switzerland
Mathieu Porceddu • MITOLOGICS Research Lab, Hôpital Robert Debré, Paris,
France; MITOLOGICS SAS, Parc Biocitech, Romainville, France
Chris S. Pridgeon • Department of Molecular and Clinical Pharmacology, MRC Centre
for Drug Safety Science, University of Liverpool, Liverpool, UK
William Proctor • Department of Safety Assessment, Genentech Inc., South San
Francisco, CA, USA
xx Contributors
Zhen Ren • Division of Biochemical Toxicology, National Center for Toxicological,

Pierre Rustin • INSERM, UMR1141-PROTECT, Hôpital Robert Debré, Paris, France
Constanze Schlott • Department of Molecular and Clinical Pharmacology, MRC
Centre for Drug Safety Science, University of Liverpool, Liverpool, UK
Gunnar Schuetz • Bayer Pharma AG, Berlin, Germany
Daniel Scotcher • University of Manchester, Manchester, UK
John Senior • Office of Surveillance and Epidemiology, Center for Drug Evaluation and
Research, U.S. Food and Drug Administration, Silver Spring, MD, USA
Md Shamsuzzaman • Office of Computational Science, Center for Drug Evaluation and
Scott Q. Siler • DILIsym Services, Inc., Research Triangle Park, NC, USA
Steven Sourbron • University of Leeds, Leeds, UK
Camilla Stephens • Unidad de Gestión de Aparato Digestivo, Servicio de Farmacología
Rolf Teschke • Division of Gastroenterology and Hepatology, Department of Internal
Medicine II, Klinikum Hanau, Hanau, Germany; Academic Teaching Hospital of the
Medical Faculty, Goethe University Frankfurt/Main, Frankfurt am Main, Germany
Bereket Tesfaldet • Office of Computational Science, Center for Drug Evaluation and
Shraddha Thakkar • Division of Bioinformatics and Biostatistics, National Center for
Weida Tong • Division of Bioinformatics and Biostatistics, National Center for
Bob van de Water • Division of Toxicology, Leiden Academic Centre for Drug Research,
John C. Waterton • Bioxydyn, Manchester Science Park, Manchester, UK; University of
Manchester, Manchester, UK; Alderley Imaging, Macclesfield, UK
Paul B. Watkins • Institute for Drug Safety Sciences, Eshelman School of Pharmacy,
The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; DILIsym
Services, Inc., Research Triangle Park, NC, USA
Steven Wink • Division of Toxicology, Leiden Academic Centre for Drug Research, Leiden
University, Leiden, The Netherlands
Min Wei Wong • Department of Molecular and Clinical Pharmacology, MRC Centre for
Drug Safety Science, University of Liverpool, Liverpool, UK
Chaoyang Zhang • School of Computer Science, University of Southern Mississippi,
Hattiesburg, MS, USA
Jieqiang Zhu • Division of Bioinformatics and Biostatistics, National Center for
Sabina Ziemian • Bayer Pharma AG, Berlin, Germany
Part I
Introduction
Chapter 1
Overview of Mechanisms of Drug-Induced Liver Injury

(DILI) and Key Challenges in DILI Research
Nabil Noureddin and Neil Kaplowitz
Abstract
The liver is an important target for foreign chemicals, such as drugs, which are metabolized and excreted
by the liver. Reactive metabolites, or in some cases parent drug, elicit a variety of biochemical consequences
such as covalent binding and oxidative stress which trigger signal transduction, transcription factors, mito-
chondrial and endoplasmic reticulum (ER) stress which can lead directly to cell death or activate adaptive
responses which mitigate these hazards. Alternatively, these stress responses may predict the development
of idiosyncratic drug-induced liver injury (IDILI). Current evidence supports the hypothesis that IDILI is
often mediated by adaptive immunity in genetically susceptible individuals which is modulated by the
robustness of immune tolerance.
Key words Hepatotoxicity, Liver injury, Adaptive immunity, Stress responses, Adaptation, Tolerance
1 Introduction
Drug-induced liver injury (DILI) is a diagnosis of exclusion which

manifests as a spectrum of clinical presentations such as acute hepa-
tocellular liver injury presenting as acute hepatitis, cholestatic jaun-
dice, nodular regenerative hyperplasia, sinusoidal obstruction
syndrome, steatohepatitis, or subclinical injury which is detected
during routine testing of serum chemistries [1, 2]. DILI is infre-
quently observed in clinical practice with an incidence ranging
from 0.014% in a French population-based cohort study, 0.019%
in the Iceland population, to 1.4% in an in-patient study from
Switzerland [3–5]. Despite its rarity, because of the wide use of
medications, DILI remains an important clinical problem.
Although most of the DILI seen postmarketing is due to drugs
approved before 1990 (Hoofnagle, personal communication),
DILI remains an ongoing problem for the pharmaceutical industry
during preclinical and clinical drug development. New drugs with
DILI potential are usually identified in preclinical and premarketing
Minjun Chen and Yvonne Will (eds.), Drug-Induced Liver Toxicity, Methods in Pharmacology and Toxicology,
https://doi.org/10.1007/978-1-4939-7677-5_1, © Springer Science+Business Media, LLC, part of Springer Nature 2018
3
4 Nabil Noureddin and Neil Kaplowitz
clinical development due to the vigilance of regulatory bodies and

Industry.
DILI imposes major clinical, economic, regulatory, and scien-
tific challenges. DILI is the leading cause of acute liver failure
(ALF) in the United States. In fact, more than half of all ALF cases
in the USA are a result of DILI, most of which are due to acet-
aminophen [6], but idiosyncratic DILI represents an important
contributor [7]. According to Liver Tox analysis which excluded
drugs marketed in the past 5 years, of 673 marketed drugs evalu-
ated, 53% had published convincing cases of DILI [8]. It is one of
the most frequently cited reasons for drug nonapproval, with-
drawal, abandonment, and postmarketing regulatory actions [9].
Mainly because of the dreaded risk of ALF and its reliable predic-
tor, Hy’s law, much effort is made to identify or predict the risk
during preclinical drug development by the pharmaceutical
industry.
DILI can be broadly divided into predictable, dose dependent,
direct (intrinsic) toxicity, such as acetaminophen (APAP) toxicity, and
unpredictable or idiosyncratic DILI (IDILI), such as isoniazid and
amoxicillin-clavulanic acid. This chapter will provide a broad over-
view of the mechanisms of DILI, and the key challenges in the field.
2 Mechanisms and Pathogenesis
The central role of the liver in removal of lipophilic drugs and their
hepatic metabolism places the liver as a prime target for reactive
metabolites of drugs. After the exposure to reactive metabolites, or
in some cases the parent drug, the ensuing fundamental processes
in DILI are biochemical and organelle stress and/or the death of
hepatocytes accompanied by inflammation (innate immunity) and,
in many cases, the participation of the adaptive immune system. All
these processes are potentially mitigated by biochemical and immu-
nological adaptive responses. The cascade of events that lead to
direct hepatotoxicity or IDILI have many similarities in the
upstream processes but fundamental differences which are deter-
mined by the individual drug and host factors, especially genetic
[10–12].
3 Direct Hepatocyte Toxicity
Drugs or reactive metabolites can cause intrinsic predictable toxicity

by covalent binding to intracellular proteins, generating reactive oxy-
gen species (ROS), and inducing organelle stress (such as endoplas-
mic reticulum (ER) and mitochondrial stress). If the stress is minor,
organelle adaptive responses (such as the unfolded protein responses
in the ER or mitochondria) will compensate and the development of
Overview of DILI 5
the injury will be dampened. If these responses are overwhelmed,

organelle stress can activate the intrinsic pathway of apoptosis via
mitochondrial outer membrane permeabilization (MOMP) or lead
to necrosis by mitochondrial permeability transition (MPT) and cell
death will occur [12]. The roles of other forms of cell death in DILI,
such as necroptosis, ferroptosis, or pyroptosis are not well under-
stood. Understanding the mode of cell death and mechanisms lead-
ing to cell death is critical for developing therapeutic strategies to
treat DILI before it becomes severe (Hy’s law or ALF).
3.1 Acetaminophen The most prominent example of direct hepatotoxin is acetamino-

(APAP) Toxicity phen (APAP). A brief summary of the cascade of events in acet-
aminophen metabolism and toxicity follows, which illustrates some
of the critical events in direct intrinsic toxicity.
The major metabolites of APAP are the glucuronide and sul-
fate conjugates, while a minor fraction is converted in the liver by
the cytochrome P450 system (mainly CYP2E1) to a highly reactive
toxic electrophilic arylating metabolite, NAPQI. NAPQI is nor-
mally quickly inactivated by being preferentially conjugated with
reduced glutathione in the liver. When large doses of APAP are
ingested, NAPQI production increases and glutathione becomes
depleted [13]. The dose of APAP sufficient to induce toxicity in
humans is very variable and depends on the many known and
unknown factors that influence APAP metabolism and the down-
stream events that induce injury and repair. NAPQI can covalently
bind to cell protein thiols and also can oxidize them leading to the
formation of inter-protein crosslinking, disulfide bridges or mixed
disulfides [14]. This causes ER stress [15] but the contribution of
ER stress in APAP toxicity has not been clearly elucidated. NAPQI
is sufficiently stable so as to enter the mitochondria, where it leads
to impairment in electron transport, resulting in the generation of
ROS [16]. NAPQI and consequent mitochondrial-derived ROS
damage mitochondrial DNA, and the release of mitochondrial
ROS activates upstream kinases such as GSK3β [19], RIPK1 [21],
PKC [20], MLK3 [23], ASK1 [24] and MKK4 [25] leading to
c-Jun N terminal Kinase (JNK) activation in the cytoplasm [16–
18]. Activated JNK (p-JNK) then binds to its target Sab [22] and
phosphorylates it on the outer mitochondrial membrane, leading
to the intermembrane release of protein tyrosine phosphatase type
6 (PTPN6) from Sab. PTPN6 dephosphorylates and inactivates
Src in the intermembrane space [22]. Active Src is required to
maintain electron transport in the inner membrane. When Src is
inactivated, the ETC chain is blocked and ROS production is
amplified, ultimately leading to MPT. This results in the collapse of
mitochondrial membrane potential, and thus the cessation of ATP
synthesis, as well as to the release of mitochondrial proteins which
damage nuclear DNA. Necrotic cell death ensues, characterized by
cell swelling and lysis, referred to as oncosis.
3.2 Cellular Stress When exposure is sufficient, many possible biochemical and organ-
Responses elle stress responses are triggered by reactive metabolites which are
and Adaptive generated in hepatocytes. These mechanisms can induce cell dys-
Responses in DILI function, potentially generate danger signals such as danger-
associated molecular patterns (DAMPS), sensitize hepatocytes to
death receptor-induced cell death, or induce sufficient stress to
mediate hepatocyte death through intrinsic death mechanisms.
Alternatively, hepatocytes have a variety of adaptive mechanisms
which can arrest the progression of cell dysfunction or lethality.
The major stressors and adaptive mechanisms are listed in Table 1.
Reactive metabolites can undergo covalent interaction with pro-
teins or induce redox perturbations leading to oxidative stress.
These upstream biochemical events play a role in causing or wors-
ening organelle dysfunction in the ER and mitochondria.
Hepatotoxic drugs commonly induce oxidative stress, ER stress,
and mitochondrial stress (any or all). Aside from a pivotal role for
ROS generated in mitochondria, accumulation of bile acids due to
drug or metabolite inhibition of BSEP may play an important role,
not only in inhibiting bile secretion (cholestasis), but in affecting
ER and mitochondrial function [26]. Although less is known about
the stress-inducing effects of fatty acids in the context of DILI,
saturated fatty acids also impair ER and mitochondrial function
[27]. A key feature of all these biochemical and stress responses is
the involvement of signaling kinases, such as MAPK, in causing or
responding to organelle and oxidative stress to perpetuate and
amplify cellular dysfunction [28].
Table 1
Intracellular stress responses and adaptive responses
Stress initiator Adaptive responses

CYP-mediated reactive metabolite formation CYP inactivation
Enhanced detoxification
Reactive oxygen species (redox perturbations Antioxidant defense
and signal transduction) [Nrf2, etc.]
Mitochondrial impairment Mitophagy, fission/
fusion, biogenesis and
UPRMito
ER stress UPRER
BSEP inhibition (bile acid toxicity) FXR mediated
enhancement of bile
acid export
Innate immunity, cytokines, chemokines, Anti-inflammatory
inflammation responses
Overview of DILI 7
Intracellular adaptive responses, when not successful in restoring

homeostasis, might sensitize “stressed hepatocytes” to greater
immune-mediated toxicity and T cell or cytokine induced apopto-
sis. Similar hypotheses can be generated for adaptation to ER
stress, commonly seen in response to covalent binding, as well as
adaptive responses to mitochondrial stress. In both instances the
cell responds to organelle specific stress through unfolded protein
responses (ER or mitochondria), which upregulate the transcrip-
tion of chaperones and improve protein folding. In addition, dam-
aged mitochondria elicit other adaptive responses such as mitophagy
(a form of autophagy selectively involving damaged, ROS produc-
ing mitochondria) to remove them, or biogenesis to replace them.
Retrograde signaling from stressed mitochondria or ER leads to
transcriptional programs for both protective UPR and organelle
biogenesis to replace the damaged organelles removed by nonse-
lective or selective (mitophagy) autophagy.
UPRER retrograde signaling mainly occurs through activation
of transcription factors such as sXBP1 and ATF6 which induce
chaperones which mitigate impaired folding. At the same time
translational arrest occurs through the activation of ER PERK
which reduces client load. When these adaptive mechanisms fail,
the ER signals apoptosis through the activation of JNK, which
along with Ca2+ released from the ER targets mitochondria leading
to ROS production and intrinsic cell death (apoptosis) mediated
by Bcl family mediated permeabilization of the outer membrane of
mitochondria [29, 30].
UPRmito has been more recently elucidated and involves a novel
regulatory mechanism of mitochondrial protease mediated degrada-
tion of cytoplasmic proteins taken up by normal mitochondria. For
example, ATFS-1 is a transcription factor with both mitochondrial
and nuclear localization peptide sequences. Mitochondrial uptake
and degradation dominates under basal conditions. However, when
its mitochondrial uptake is impaired (depolarized or damaged mito-
chondria), this transcription factor is stabilized and translocates from
the cytoplasm to the nucleus to activate expression of mitochondrial
chaperones and import machinery [31]. Interestingly, this type of
novel protein regulatory turnover mechanism also plays a role in
mitophagy. PINK1 is a kinase which continuously enters mitochon-
dria and is degraded. When mitochondria depolarize, PINK1 stabi-
lizes on the outer membrane and recruits and phosphorylates
PARKIN, an E3 ligase which ubiquitinates outer membrane pro-
teins which target mitochondria for mitophagy after p62 binding to
the ubiquitinated proteins. PINK1 also inactivates mitochondrial
fusion allowing fission to occur so that mitochondrial fragments are
able to undergo mitophagy [32]. The regulation and importance of
fission/fusion in DILI is largely unexplored.
The role of autophagy/mitophagy has been studied in
APAP induced hepatotoxicity. APAP resulted in formation of
autophagosomes that engulfed mitochondria and pharmacological

inhibition of autophagy by 3-methyladenine or chloroquine
exacerbated APAP toxicity while this was attenuated by rapamycin-
induced enhanced autophagy, even if administered two hours after
APAP [33].
Direct toxicity is generally identified readily in preclinical
and/or the early phase of clinical testing and only is acceptable in
the extension of drug development when the benefit far outweighs
the risk. The latter scenario mainly applies to cancer chemotherapy
drugs. An overview of the principles of direct hepatotoxicity is
illustrated in Fig. 1. These concepts of cellular stress and death also
seem to be relevant to IDILI. There are many approaches to pre-
clinical screening of drugs which have been validated using panels
of drugs known to cause IDILI compared to drugs which have no
or minimal risk. The study models include isolated mitochondria
or microsomes, hepatocytes, liver cancer cell lines, collaborative
cross of inbred mouse strains, humanized mice, organoids, liver on
a chip, micropatterned culture, iPS derived liver-like cells, and
other emerging technologies. Assessment for various hazards
include transcriptomics, cellular respiration, ATP, ROS, covalent
binding, apoptosis or necrosis, and BSEP inhibition with the aim
of identifying hazards such as oxidative stress, lipid peroxidation,
transcriptomic changes, ER or mitochondrial stress, or the footprint
Parent Drug Covalent Binding

or Oxidative Stress
Reactive Proteostatic Stress
Metabolite
Signal transduction
Organelle Stress
Mitochondrial, ER,
Nuclear
UPR-ER, UPR-Mito,
Autophagy,
Anti-inflammatory
balance
Overwhelmed Effective
Adaptation Adaptation
Necrosis or Dampening of
Apoptosis Injury
Fig. 1 Pathogenesis of direct hepatotoxicity

Overview of DILI 9
of these hazards as reflected in robust adaptive responses. The chal-

lenging aspect of the findings relates to the reason for good predic-
tive performance of most of these model systems in identifying
IDILI risk in the face of the fact that these approaches are largely
identifying direct toxicity and may not necessarily reflect the idio-
syncratic mechanism. Are these predictable hazards a surrogate for
drugs which are potentially immunogenic without informing on
specific mechanism or are these hazards important contributing
factors to the development of adaptive immunity through the gen-
eration of danger signals and/or are these hazards contributing to
the unmasking of IDILI by sensitizing to adaptive immune-
mediated killing? Further complicating these possibilities is the
question of whether variations in the adaptive responses to cellular
hazards contribute to susceptibility to direct or idiosyncratic DILI.
4 IDILI
The pathophysiology of IDILI is multifactorial, involving drug/

pharmacological factors, host factors, and factors affecting the
adaptive immune system. Current evidence strongly favors the
concept that IDILI is usually mediated by the adaptive immune
system. Recent work has shown that many examples of IDILI are
associated with genetic susceptibility in the MHC genes [34].
However, in most examples only a small proportion of individuals
carrying the risk allele develop liver injury.
4.1 Factors ●● Pharmacological: Certain drug properties such as dosage and

Contributing lipophilicity have been associated with IDILI. In fact, drugs
to Development that are both taken at a high dose (greater than 50–100 mg/
of IDILI day) and have a calculated octanol-water partition coefficient
(log P > 3) rendering them lipophilic have a higher positive
predictive value for inducing toxicity than a dose alone, indi-
cating the need for a threshold level of hepatic exposure [35].
Thus, although IDILI is not strictly dose-related, a dose
threshold to meet some level of exposure to the drug, its
metabolites, and or its hazards appears to be needed for the
development of adaptive immune response.
●● Host factors: Age and sex are well-known risk factors for toxic-
ity of specific drugs. It is possible that age influences the adap-
tive immune response. Of course, medication use increases
with age and polypharmacy is more prevalent [36]. Women
tend to be at higher risk for IDILI in many studies. However,
in the Spanish DILI registry, Lucena et al. did not find an asso-
ciation between female sex and overall increased incidence of
DILI [37].
●● Hepatic metabolism and transport: Most often, the first step for
an IDILI event is for the parent drug to form a reactive metab-
olite capable of covalently binding intracellular proteins and
generating cellular stress. There is considerable individual vari-
ation in the activity of the cytochromes P-450 (CYP) deter-
mined by environmental and genetic effects. Similarly, exposure
may be greatly influenced by the status of phase 2 conjugation
and phase 3 transporters which are also subject to environmen-
tal and genetic influences. Surprisingly, GWAS and exome
sequencing studies have only infrequently found genetic poly-
morphisms in IDILI related to hepatic metabolism or trans-
port [38, 39]. However, nongenetic variations in hepatic
metabolism and transport likely play a role in susceptibility to
direct toxicity and by extension to hazards elicited by IDILI
drugs. The fact that hazards in preclinical testing are usually
studied at high drug concentrations could obscure the contri-
bution of variations in drug metabolism and transport to risk.
Certainly, potency of BSEP inhibition in predicting IDILI sug-
gests that effects of transporters maybe be of importance.
●● Genetic variations and polymorphisms in human leukocyte anti-
gens: The idiosyncratic nature of most drug reactions has long
been viewed as evidence of a genetic predisposition to hepato-
toxicity. Polymorphisms in HLA genes have been clearly dem-
onstrated to be associated with many recent IDILI drugs [34].
The implication of these studies is that IDILI is the result of
the activation of an adaptive immune response. These HLA
haplotype associations suggest that DILI occurs due to a
genetic predisposition to an adaptive immune response due to
the presentation and recognition of a drug-related antigen.
Although HLA restriction has been evident for years, the
underlying mechanisms of the immune response have not been
fully elucidated. Several hypotheses of the immune system acti-
vation in IDILI have been proposed [34]. These are supported
by earlier studies identifying the occurrence of anti-drug
hapten antibodies and autoantibodies in some cases as well as
by the occurrence of systemic hypersensitivity as evidenced by
fever, rash, eosinophilia with a latency of days to a few weeks in
some cases. However, it is important to recognize that many
examples of IDILI are not accompanied by such systemic
manifestations of hypersensitivity and exhibit longer latency of
months. It is remarkable that these IDILI scenarios selectively
involving the liver were formerly considered to be due meta-
bolic idiosyncrasy. This is not to say that metabolic idiosyn-
crasy does not occur due to cumulative direct effects of certain
drugs, for example nucleosides and amiodarone toxicity.
Overview of DILI 11
4.2 Hypotheses ●● Hapten hypothesis: This postulates that certain drugs are metab-
of Immune System olized to reactive compounds which can bind to endogenous
Activation proteins and form neoantigenic or “hapten” peptides that are
and Involvement presented to and recognized as foreign antigens by the immune
in IDILI system of certain individuals with HLA polymorphisms [34,
40]. This is probably the most common mechanism. In certain
cases, the parent drug (e.g., flucloxacillin [41]) may form
covalent interactions with a peptide directly in the MHC
groove. However, covalent binding probably occurs in nearly
all exposed individuals including those with HLA risk, whereas
even mild DILI occurs in only a small minority.
●● Pharmacological interaction (p-i) hypothesis: This proposes that
certain drugs can directly form noncovalent interactions with
MHC molecules leading to the activation of the immune sys-
tem [42, 43]. It is likely that the initial binding of the drug to
the MHC molecule is labile, and serves as a scaffold for a T cell
receptor (TCR) interaction of much higher relative affinity.
This TCR interaction is capable of generating an immunological
response, as it involves T cell activation. However, the specific
sites of drug binding on the MHC-peptide complex remain
unresolved for many drugs.
●● The altered peptide repertoire hypothesis: This model suggests
that certain drugs can cause mistargeting of endogenous
peptides to the wrong HLA leading to autoimmunity. The
mistargeting is drug dependent and may involve covalent or
noncovalent binding of the parent drug to the MHC peptide
binding groove. The mechanism of abacavir skin toxicity is the
best example [44, 45].
●● Multiple determinant hypothesis: An alternative hypothesis for
IDILI is that multiple risk factors (such as polymorphisms, age,
gender, preexisting conditions) could overlap together to
induce DILI [46–48]. The mouse model of halothane-induced
liver toxicity can be used as example. Among the known human
risk factors for halothane hepatitis are female gender, middle
age, genetic predisposition, and multiple exposures. Therefore,
unless all conditions are met and the multiple determinants are
fulfilled IDILI will not occur which may partly explain why the
disease is so rare [49]. Nevertheless, this hypothesis is most
likely a precursor for the development of adaptive immunity in
susceptible individuals.
●● Inflammatory stress hypothesis: The unpredictable nature of
idiosyncratic DILI may also suggest that there could be another
event occurring concomitantly with drug therapy. This raises
the possibility that IDILI reactions could be unmasked by
inflammation concomitantly occurring during drug therapy,
which could interact with the action of the drug and escalate
into liver injury. Such a response is often characterized by

inflammatory cell infiltrates within liver lesions of patients
suffering from IDILI. These inflammagens bind to “pattern
recognition receptors” such as Toll-like receptors (TLRs) on
immune system cells, which initiate the activation of transcrip-
tion factors and the expression of inflammatory mediators such
as TNFα and IFNɣ [46–50]. This seems most plausible in the
in the context of danger signals to promote adaptive immu-
nity in genetically predisposed individuals. However, the
adaptive immune response may not only be costimulated by
cytokines, but may also lead to production of cytokines which
are effectors of hepatocellular stress and death (e.g., TNF and
IFNɣ mediated necrosis). Thus, immune mediated cell death,
the key manifestation of serious IDILI may be mediated by a
repertoire of effector mechanisms including TCR engage-
ment, granzyme/porin, FasL, cytokines, and antibody/
complement.
4.3 Immune- Only a small proportion of individuals with susceptible HLA geno-
Tolerance types develop clinically significant liver injury when exposed to
and Adaptation IDILI drugs. The adaptation hypothesis has been put forth as an
explanation for why only a small percentage of susceptible indi-
viduals develop either no evidence of liver injury or overt IDILI
and severe injury, while the majority with susceptible genotypes
develop only mild abnormalities that usually resolve spontaneously
despite continuation of the drug. This spontaneous resolution is
referred to as clinical adaptation. This adaptation may be the result
of liver’s constant state of immune tolerance in order to avoid
inflammatory reaction due to its routine exposure to foreign anti-
gens [21] (Fig. 2).
The mechanisms of immune-tolerance can be broken down to
the following key events: control of antigen presentation, clonal
deletion (apoptosis of antigen-specific T cells) and immune devia-
tion (switching fromTh2 to Th1 predominance).
The liver microenvironment plays a crucial role in the induc-
tion of immune tolerance toward dietary and foreign antigens.
The liver contains various cell types, hepatocytes, along with the
cholangiocytes, are the functional components of the liver. Other
cell types referred to as nonparenchymal cells (NPC), essential to
normal biologic and immunologic functions, include liver sinusoi-
dal endothelial cells (LSECs, which constitute the wall of the liver
sinusoids), Kupffer cells (KCs) which are resident liver macro-
phages, stellate cells (HSCs) which are pericytes found in perisinu-
soidal space, liver-associated lymphocytes and dendritic cells.
LSECs function as a barrier between leukocytes or other macro-
molecules present in the sinusoidal lumen and hepatocytes, thus
preventing direct contact between leukocytes and hepatocytes.
LSECs take up antigens from the sinusoids for processing and
Overview of DILI 13
Parent Drug
or Host/Pharmacological Factors
Reactive
Metabolism Hapten vs P-I vs altered peptide
repertoire vs multiple determinant
vs inflammatory stress hypothesis
Susceptible HLA
Adaptive Immune
Response
Insufficient Immune Tolerance

Tolerance and Adaptation
No or
Overt
Mild/Transient
IDILI
Injury
Fig. 2 Importance of status of immune tolerance in the pathogenesis of IDILI
antigen presentation. They can induce cytokine expression and

proliferation and activation of CD4+ T cells. KCs, which are spe-
cialized macrophages, are located mainly in the periportal sinu-
soids so they can phagocytose and eliminate antigens and
pathogens entering the liver parenchyma via portal venous blood
from the intestines. KCs also play a pivotal role in regulating the
liver’s homeostasis in the face of constant exposure to ingested
antigens. The liver’s immune tolerance is dependent on the auto-
crine and paracrine effects of cytokines secreted by KCs as well as
on LPS stimulation of immune cells and antigen presenting cells
(KC and LSECs particularly). LPS from gut accompanies ingested
food antigens and has been shown to have immune-tolerogenic
properties. KCs and LSECs express cytokines such as IL-10,
TGFβ, TNF, and prostaglandins either constitutively or in
response to LPS, resulting in downregulation of leukocyte adhe-
sion to LSECs, expansion of regulatory T cells (T-regs), and abro-
gation of T cell activation, all of which lead to an increased
immune tolerance in the liver [21, 51].
Another proposed mechanism of peripheral immune-tolerance
induction by the liver is the phenomenon of clonal deletion or
induction of antigen-specific T cell apoptosis in the liver [52, 53].
While the elimination of T cell populations seems an attractive
explanation, it does not seem to be the whole story since tolerance
can be transferred from one animal to another. This can be achieved
by adoptive transfer of γδ T cells, which suggests that the mechanism
of this phenomenon is more complex and that tolerance is mediated,

at least in part, by immune deviation as opposed to mass T cell
elimination [21].
Despite these recent advances in proof of principle studies
demonstrating the potential role of immune tolerance, the exact
underlying mechanism of defective clinical adaptation, even in
those individuals with HLA risk, and how it results in IDILI
remains unknown. However, many interesting associations are
apparent, such as the frequency of IDILI with antibiotics (nine out
of the top ten agents causing IDILI in the DILIN database are
antimicrobials) [54]. Given the strong evidence for the tolerogenic
properties of LPS on antigen presentation and cytokine secretion,
it is intriguing to hypothesize that the antibiotic effects on gut
microflora and changes in LPS exposure may contribute to defec-
tive adaptation. The changes in gut microbiota may also have
effects on the phenotypes and functions of regulatory immune
cells in the liver immune system, e.g., KC polarization (pro- or
anti-inflammatory), T-reg expansion/frequency, hepatic stellate
cells, etc. Furthermore, the microbiome can influence drug toxic-
ity and the liver not only by the tolerogenic properties of LPS, but
by affecting drug metabolism. It is important to point out that
these are only associations and intriguing as hypotheses but no
evidence of causality exists [54]. Furthermore, complicating the
role of the microbiome are its effects on drug metabolism and
enterohepatic cycling of drugs which may influence exposure in
the liver [55, 56]. In addition, since mitochondria, derived from
ancestor protobacteria, retain similar machinery for protein syn-
thesis, one could speculate that antibiotics have similar toxic effects
on liver mitochondria, possibly inducing a costimulatory effect on
adaptive immune response.
More recently several studies and animal models have shown
that when the intrinsic liver autoimmunity checkpoints are experi-
mentally bypassed, drugs that normally would not result in liver
injury or only cause transient DILI, caused T cell activation with
persistent and more severe DILI, which strengthens the immune
tolerance and clinical adaptation theory [57–59].
It is tempting to speculate that clinical adaptation, during which
liver tests reflecting mild injury resolve despite continued drug
ingestion, is mainly driven by the development of immune tolerance
which dampens the injury and conversely the inadequate develop-
ment of tolerance may explain the progression to Hy’s law and
severe liver injury. Indeed, one could even entertain the hypothesis
that hypertolerant individuals begin to dampen injury before it can
be detected. Thus, despite the low incidence of clinical adaptors and
even lower incidence of nonadaptors among those who have a
genetic predisposition to an adaptive immune response to an IDILI
drug, it is likely that far more of these individuals exhibit covalent
binding. They may not progress to even mild DILI because of an
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The examination of the dialects is perhaps the most original
feature in the book; that Dante did not recognise that what was
destined to be the literary language of Italy was, in reality, the
Tuscan dialect, but adopted instead the theory of a conventional or
artificial Italian, was largely due to his theories being based upon the
lyrical poetry of his predecessors, in which he seemed to find this
abstraction realised; for, though natives of different regions of Italy,
they used—or, in the form in which their poems came to him,
appeared to have used—a common literary language. Nevertheless
in the Divina Commedia, which was to codify the national language,
Dante recognised that he himself was speaking Tuscan (Inf. xxiii. 76,
Purg. xvi. 137).
Book II.—The unfinished second book is of the utmost value to
the student of Italian poetic form. It makes us realise, too, how
zealously Dante sought out technical perfection, studying subtle
musical and rhythmical effects, curiously weighing the divisions of
his stanzas, balancing lines, selecting words, harmonising syllables.
No less noteworthy are his modest references to his own work and
his generous appreciation of that of others, his predecessors and
contemporaries, with reference to whose poems, as well as to his
own, he illustrates his maxims. There is a certain limitation in that
Dante conceives of poetry as only lyrical and written to be set to
music (ii. 4), recognising only the most elaborate and least
spontaneous forms of lyrical poetry—the Canzone (of which the
Sestina is a variety), the Ballata, the Sonnet (ii. 3). There is no hint of
that splendid rhythm, at once epical and lyrical, in which the Divina
Commedia was to be written; though it is possible that Dante would
have dealt with it in the fourth book, in which he intended to treat the
discernment to be exercised with a subject fit to be sung in the
“comic” style, in which sometimes the “middle” and sometimes the
“lowly” vernacular may be used (ii. 4), and also, dealing with poems
in the “middle” vulgar tongue, to treat specially of rhyme (ii. 13). The
third book would perhaps have been concerned with the use of the
illustrious vernacular in Italian prose (ii. 1.)
The illustrious vulgar tongue having been found, Dante proceeds
thus to show the noblest use to which it can be put by the poet. Only
three subjects are sufficiently exalted to be sung in this stateliest
form of Italian speech, this highest vernacular: Salus, Venus, Virtus;
or those things which specially relate to them: the rightful use of
arms, the fire of love, the direction of the will; and the first of these
themes had not been handled, according to Dante, by any Italian
poet. He cites Bertran de Born as having written on arms, Arnaut
Daniel and Cino da Pistoia on love, Giraut de Borneil and “the friend
of Cino” (himself) on rectitudo (ii. 2). Of the three legitimate lyrical
forms the canzone is noblest, and contains what Rossetti called the
“fundamental brainwork” of the most illustrious poets (ii. 3). And the
ballata is nobler than the sonnet. It is in the canzone alone, in the
“tragic” or highest style, that these sublime themes are to be sung;
the style in which the stateliness of the lines, the loftiness of the
construction, and the excellence of the words agree with the dignity
of the subject. In this superexcellent sense, a canzone is a
composition in the loftiest style of equal stanzas, without a refrain,
referring to one subject.[21] And the rest of the book is occupied with
rules for its proper construction; the different lines to be used, the
choice of words, the structure of the various types of stanza, in which
the whole art of the canzone is contained, the arrangement of
rhymes; the work breaking off at the point where Dante was about to
treat of the number of lines and syllables in the stanza. It is
noteworthy that, though he illustrates his practical rules by examples
from the Provençal troubadours, his Italian predecessors and
contemporaries, and his own canzoni, the great Latin poets are set
up as models: “The more closely we imitate these, the more correctly
we write poetry” (ii. 4). There is some indication that the De Vulgari
Eloquentia would have been dedicated to Cino da Pistoia as the Vita
Nuova had been to Guido Cavalcanti.
Date of Composition.—The De Vulgari Eloquentia was probably
written about the same time as the Convivio or slightly earlier. From
a mention of the Marquis Giovanni of Monferrato apparently as living
(V. E. i. 12), who died in January (?) 1305, it has been supposed that
Book i. cannot be much later than the beginning of that year. Dante’s
evident friendly feeling for Bologna (which altered before he wrote
the Commedia) may be connected with the time when the Florentine
exiles were welcomed in that city, before the decree of expulsion in
1306. It has sometimes been thought that Book ii. may be a much
later piece of work, produced as a poetical textbook at Ravenna in
Dante’s last years, and broken off, as Boccaccio suggests, by his
death. Nevertheless, when the tone of the work and the probable
dates of the lyrics quoted be taken into account, it seems more
probable that what we have of the De Vulgari Eloquentia was written
between 1304 and 1306; it represents part of the labours which were
interrupted by the advent of Henry VII., or abandoned when the poet
turned to the Divina Commedia.
2. The “Monarchia”
The Empire.—Upon all the political life of mediaeval Italy lay the
gigantic shadow of a stupendous edifice, the Holy Roman Empire.
Although the barbarians had struck down the body of the Empire of
Rome, the spirit of Julius Caesar was mighty yet, as in
Shakespeare’s tragedy. The monarchy of Augustus, of Trajan, of
Constantine and Justinian, still lived; not in the persons of the
impotent Caesars of Byzantium, but in those of the successors of
Charlemagne. From the coronation of Otto the Saxon (962) to the
death of the Suabian Frederick II. (1250), the mediaeval western
world saw in the man whom the Germans recognised as their
sovereign the “King of the Romans ever Augustus,” the Emperor-
elect, who when crowned at Rome would be “Romanorum
Imperator,” the supreme head of the universal Monarchy and the
Vicar of God in things temporal, even as the Pope was the supreme
head of the universal Church and the Vicar of God in things spiritual.
In the eyes of Dante, the Papacy and the Empire alike proceeded
from God, and were inseparably wedded to Rome, the eternal city;
from which as two suns they should shed light upon man’s spiritual
and temporal paths, as divinely ordained by the infinite goodness of
Him from whom the power of Peter and of Caesar bifurcates as from
a point (Purg. xvi. 106-108, Epist. v. 5).
Papal Claims.—With the increase of their temporal power, the
successors of Hildebrand, in the twelfth and thirteenth centuries, had
extended their authority from spiritual into purely secular regions. For
them the imperial dignity was not of divine origin, but the gift of the
Church to Charlemagne and his German successors. “What is the
Teutonic King till consecrated at Rome?” wrote Adrian to Frederick
Barbarossa: “The chair of Peter has given and can withdraw its
gifts.” In the interregnum that followed the fall of the house of Suabia,
the Popes had claimed to exercise imperial rights in Italy, with
disastrous results. They had joined the sword with the pastoral staff;
and the Church, by confounding in herself the two governments, had
fallen into the mire (Purg. xvi. 109-112, 127-129). And this tendency
in the Papacy culminated in the extravagant pretensions of Boniface
VIII., in his relations with both the Empire and France, and his
famous Bull Unam Sanctam (November 1302), declaring that the
temporal power of kings is subject to the spiritual power of the
priesthood, and directed by it as the body by the soul.
Date of the “Monarchia.”—The Monarchia is Dante’s attempt to
solve this burning mediaeval question of the proper relations of
Church and State, of spiritual and temporal authority. Although it is
undoubtedly the most famous of his prose works, the most widely
divergent views have been held as to its date of composition. If the
Vita Nuova is the most ideal book of love, the Monarchia is one of
the most purely idealistic works ever written on politics. Even as
Beatrice is the most glorious lady of the poet’s mind, la gloriosa
donna de la mia mente, so the temporal monarchy or Empire is to be
considered by the poet in its ideal aspect according to the divine
intention, typo et secundum intentionem (Mon. i. 2). Like the Vita
Nuova, and unlike any other of Dante’s longer works, the Monarchia
contains no mention of the poet’s exile, and no explicit references or
allusions to contemporary events or persons. From this, and other
considerations, it has sometimes been held that the Monarchia was
written during his political life in Florence. Boccaccio, on the other
hand, declares that Dante made this book on the coming of Henry
VII., and the trend of criticism to-day is to accept 1313 as the
approximate date. There are, however, scholars who consider it
more probable that the Monarchia was written towards the close of
the poet’s life.
Book I.—The Monarchia is divided into three books,
corresponding to the three questions to be answered touching this
most useful and least explored amongst occult and useful truths, the
knowledge of the temporal monarchy (i. 1). In its ideal sense, the
temporal Monarchy, or Empire, is defined as “a unique princedom
extending over all persons in time, or in and over those things which
are measured by time” (i. 2). And the first question arising
concerning this temporal Monarchy is—whether it is necessary for
the well-being of the world.
The proper function of the human race taken as a whole, the
ultimate end or goal, for which the eternal God by His art, which is
nature, brings into being the human race in its universality, is
constantly to actualise or bring into play the whole capacity of the
possible intellect, for contemplation and for action, for speculation
and for operation (i. 3). And, for this almost divine function and goal,
the most direct means is universal peace (i. 4). Since it is ordained
for this goal, the human race must be guided by one ruling power,
the Emperor, with reference to whom all its parts have their order; in
subjection to whom, the human race becomes in its unity most like to
God (i. 5-9). There must be some one supreme judge to decide by
his judgment, mediately or immediately, all contentions; and such a
judge can only be the Monarch (i. 10).
Again, the world is best disposed when justice is paramount
therein; but this can only be under the Monarch or Emperor, who
alone, free from covetousness and supreme in authority, will have
the purest will and the greatest power to practise justice upon the
earth (i. 11). Under him the human race will be most free, since it will
have the fullest use of freewill, the greatest gift of God to man (i. 12).
He alone, adorned with judgment and justice in the highest degree,
will be best disposed for ruling, and able to dispose others best (i.
13). From him the particular princes receive the common rule by
which the human race is guided to peace; his is the dominating will
that rules the wills of mortals, disposing them to unity and concord (i.
14, 15). All these and other reasons show that, for the well-being of
the world, it is necessary that there should be the Monarchy. And
they are confirmed by the sacred fact that Christ willed to become
man in the “fullness of time,” when the world was blessed with
universal peace under the perfect monarchy of Augustus, the
seamless garment that has since been rent by the nail of cupidity (i.
16).
To the modern mind the first book of the Monarchia is the most
important. The conception that the goal of civilisation is the realising
of all human potentialities is one of abiding significance. Divested of
its mediaeval garb, the Empire itself becomes a permanent court of
international justice, a supreme and impartial tribunal of international
arbitration. Within such a restored unity of civilisation, nations and
kingdoms and cities will develop freely and peacefully, in accordance
with their own conditions and laws (cf. i. 10, 12, 14, and Conv. iv. 4).
Here Dante anticipates what Mazzini called the “United States of
Europe,” or, more broadly, “Humanity.”
Book II.—The second book answers the question whether the
Roman people took to itself this dignity of Monarchy, or Empire, by
right. But right in things is nothing else than the similitude of the
Divine Will, and what God wills in human society is to be held as true
and pure right. God’s will is invisible; but it is manifested in this
matter by the whole history of Rome (ii. 1, 2). The surpassing
nobleness of Aeneas, and therefore of his descendants (ii. 3); the
traditional miracles wrought for the Romans (ii. 4); the devotion of
the great Roman citizens from Cincinnatus to Cato, showing that the
Roman people, in subjecting the world to itself, contemplated the
good of the Commonwealth, and therefore the end of right (ii. 5, 6);
the manifest adaptation of the Roman people by nature for ruling the
nations with imperial sway (ii. 7);—all these prove that it was by right
that the Romans acquired the Empire. The hidden judgment of God
is sometimes revealed by contest, whether in the clash of champions
in an ordeal or in the contention of rivals striving together for some
prize (ii. 8). Such a prize was the empire of the world, which by
divine judgment fell to the Roman people, when all were wrestling for
it, and the kings of the Assyrians, Egyptians, and Persians, and even
Alexander himself had failed (ii. 9). Their wars, too, from the earliest
times were under the form of an ordeal; and Divine Providence
declared in their favour. Thus arguments resting on principles of
reason prove that the Roman people acquired the supreme and
universal jurisdiction by right (ii. 10, 11). And arguments based upon
principles of Christian faith support it. Christ, by His birth under the
edict of Augustus, confirmed the imperial jurisdiction from which that
edict proceeded; and, by His death under the vicar of Tiberius, He
confirmed the universal penal jurisdiction of the Emperor over all the
human race which was to be punished in His flesh (ii. 12, 13). “Let
them cease to reproach the Roman Empire, who feign themselves to
be sons of the Church; when they see that the Bridegroom, Christ,
thus confirmed it at either limit of His warfare” (i.e. at the beginning
and at the end of His life upon earth).
Book III.—And this rebuke to the clergy, from whom the main
opposition to the Empire proceeded, naturally leads to the great
question of the third book, the pith of the whole treatise.[22] Does the
authority of the Roman Monarch or Emperor, who is thus by right the
monarch of the world, depend immediately upon God, or upon some
vicar of God, the successor of Peter? (iii. 1, 2, 3). The stock
arguments of those who assert from passages of Scripture, such as
the creation of the sun and moon, or the two swords mentioned in St.
Luke’s Gospel, that the authority of the Empire depends upon that of
the Church, are readily brushed away (iii. 4-9). And, as for their
historical evidence, the donation of Constantine, if genuine, was
invalid; the coronation of Charlemagne was an act of usurpation (iii.
10, 11). The authority of the Church cannot be the cause of the
imperial authority, since the latter was efficient, and was confirmed
by Christ, before the Church existed (iii. 13). Neither has the Church
this power of authorising the Emperor from God, nor from herself,
nor from any Emperor, nor from the consent of the majority of
mankind; indeed, such power is absolutely contrary to her very
nature and the words of her Divine Founder (iii. 14, 15).
But it may be directly shown that the authority of the Emperor
depends immediately upon God. For man, since he alone partakes
of corruptibility and incorruptibility, is ordained for two ultimate ends
—blessedness of this life, which is figured in the Earthly Paradise,
and blessedness of life eternal, which consists in the fruition of the
Divine Aspect in the Celestial Paradise.[23] To these two beatitudes,
as to diverse ends, man must come by diverse means. For to the
first we come by philosophic teachings, provided that we follow them
by acting in accordance with the moral and intellectual virtues; to the
second by spiritual teachings, transcending human reason, as we
follow them by acting in accordance with the theological virtues,
Faith, Hope, Charity. But in spite of reason and revelation, which
make these ends and means known to us, human cupidity would
reject them, “were not men, like horses going astray in their
brutishness, held in the way by bit and rein.” “Wherefore man had
need of a twofold directive power according to his twofold end, to wit,
the supreme Pontiff, to lead the human race, in accordance with
things revealed, to eternal life; and the Emperor, to direct the human
race to temporal felicity in accordance with the teachings of
philosophy.” It is the special function of the Emperor to establish
liberty and peace upon earth, to make the world correspond to the
divinely ordained disposition of the heavens. Therefore he is chosen
and confirmed by God alone; the so-called Electors are only the
proclaimers (denuntiatores) of Divine Providence. “Thus, then, it is
plain that the authority of the temporal monarch descends upon him
without any mean from the fountain of universal authority.” Yet it
must not be taken that the Roman Prince is not subordinate in
anything to the Roman Pontiff, since this mortal felicity is in some
sort ordained with reference to immortal felicity. “Let Caesar,
therefore, observe that reverence to Peter which a firstborn son
should observe to a father, so that, illuminated by the light of paternal
grace, he may with greater power irradiate the world, over which he
is set by Him alone who is ruler of all things spiritual and temporal”
(Mon. iii. 16).
Reception of the Work.—The Monarchia remained almost
unknown until the great conflict between Louis of Bavaria and Pope
John XXII., after Dante’s death. Boccaccio tells us that the
Imperialists used arguments from the book in support of their claims,
and it became in consequence very famous. A tempest of clerical
indignation roared round it. A Dominican friar, Guido Vernani, wrote a
virulent but occasionally acute treatise, “on the power of the
Supreme Pontiff and in confutation of the Monarchy composed by
Dante Alighieri,” which he dedicated as a warning to Ser Graziolo de’
Bambaglioli, chancellor of Bologna, Dante’s commentator and
apologist. The notorious Cardinal Bertrando del Poggetto, who had
been sent as papal legate to Italy by John XXII., had the Monarchia
burnt as heretical, and followed this up—apparently in 1329—by an
infamous attempt to desecrate Dante’s tomb. In the sixteenth century
it was placed upon the Index of Prohibited Books. Dante had
anticipated this, and the splendid passage which opens the third
book of the Monarchia strikes the keynote, not only of this treatise,
but of all his life-work for what he conceived the service of God and
the welfare of man:
“Since the truth about it cannot be laid bare without putting certain
to the blush, perchance it will be the cause of some indignation
against me. But since Truth from her immutable throne demands it,
and Solomon, too, as he enters the forest of the Proverbs, teaches
us by his own example to meditate upon the truth and abjure the
impious man, and the Philosopher, teacher of morals, urges us to
sacrifice friendship for truth, therefore I take courage from the words
of Daniel, wherein the divine power, the shield of such as defend the
truth, is proffered; and, putting on the breastplate of faith, according
to the admonition of Paul, in the warmth of that coal which one of the
Seraphim took from the celestial altar and touched the lips of Isaiah
withal, I will enter upon the present wrestling-ground, and, by the
arm of Him who delivered us from the power of darkness by His
blood, will I hurl the impious and the liar out of the ring in the sight of
all the world. What should I fear, since the Spirit, coeternal with the
Father and with the Son, says by the mouth of David: ‘The just shall
be had in everlasting remembrance; he shall not be afraid of an evil
report’?”
3. The “Epistolae”
Dante tells us in the Vita Nuova that, on the death of Beatrice, he
wrote a Latin letter to the chief persons of the city, concerning its
desolate and widowed condition, beginning with the text of Jeremiah:
“How doth the city sit solitary.” Neither this nor the letter mentioned
by Leonardo Bruni, in which Dante described the fight at
Campaldino, has survived. Many epistles ascribed to Dante were
extant in the days of Boccaccio and Bruni. Bruni tells us that, after
the affair at Lastra, Dante wrote for permission to return to Florence
both to individual citizens in the government and to the people,
especially a long letter beginning: “O my people, what have I done
unto thee?” This may perhaps have been the letter which Bruni
records, in which the poet defends his impartiality when the leaders
of the two factions were banished; but there appears to have been
another, denying that he had accompanied the Emperor against
Florence. From one of these the perplexing fragment may have
come, about his want of prudence in the priorate and his service at
Campaldino. Giovanni Villani mentions three noble epistles, the style
of which he praises highly: one to the government of Florence,
“complaining of his unjust exile,” which is probably the lost letter
mentioned by Bruni; the second, to the Emperor Henry, and the third,
to the Italian cardinals, have both been preserved. Flavio Biondo, in
the fifteenth century, professes to have seen letters at Forlì dictated
by Dante, notably one addressed by the poet, in his own name and
on behalf of the exiled Bianchi, to Can Grande della Scala
concerning the reply of the Florentines to the ambassadors of the
Emperor.
There are now thirteen extant Latin letters ascribed to Dante. They
have come down to us mainly in two fourteenth-century manuscripts;
three have been preserved in Boccaccio’s handwriting in the
Laurentian MS., known as the Zibaldone Boccaccesco; nine others
in a Vatican MS., of which Boccaccio was perhaps the original
compiler. Two of these latter have also been found in another MS. of
the fourteenth century—the San Pantaleo MS. at Rome. No MS. of
the letter to Can Grande is known earlier than the fifteenth century.
[24]
Epistles I. and II.—Epistles i. and ii. are connected with Count

Alessandro da Romena, who, Bruni states, was appointed captain of
the Bianchi in their meeting at Gargonza, and whom Dante brands
with infamy in Inferno xxx. The former is addressed in the name of
Alessandro, the council and whole body of the White party, to the
Cardinal Niccolò da Prato, legate of Benedict XI., assuring him of
their gratitude and confidence, promising to refrain from hostilities in
expectation of his good offices in the pacification of Florence. It may
be accepted as an authentic document of 1304; but whether it was
written by Dante, who had perhaps already left his fellow-exiles, is
still open to question. The second is a letter of condolence to
Alessandro’s nephews, Oberto and Guido, on the occasion of their
uncle’s death, which probably occurred in the same year. Its
authenticity is highly doubtful. Both letters are found only in the
Vatican manuscript.
Epistles III. and IV.—Epistles iii. and iv. are directly connected
with the Rime. The third, which occurs in the Boccaccian autograph,
seems to be to Cino da Pistoia, affectionate greetings from the
Florentine exile to the Pistoian, explaining how one passion may be
replaced by another in the soul. It was accompanied by a poem,
which is identified with the sonnet, “Io sono stato con Amore
insieme.” If authentic, its date would be not later than 1306, when
Cino’s exile ended. The fourth letter, found in the Vatican MS., is
addressed to the Marquis Moroello Malaspina, apparently from the
Casentino, and describes in forcible language how the writer was
suddenly enamoured of a woman’s beauty. It, too, was accompanied
by a poem, evidently the canzone, “Amor, da che convien pur ch’io
mi doglia.” The more probable date is 1307 or thereabouts.[25] The
authenticity of these two letters is doubtful, but on the whole
probable.
Epistles V., VI. and VII.—Next come the three great political
letters, glorified pamphlets on the enterprise of Henry of Luxemburg.
Letter v., the manifesto to the Princes and Peoples of Italy, seems to
have been written in September or October, 1310, before Henry
crossed the Alps. It announces the advent of Henry, the bridegroom
and glory of Italy, as bringing a new era of peace, declares the
rightful authority and historical sanctity of the Empire, exhorting the
peoples to free and joyous submission, and those who, like the writer
himself, have suffered injustice to be merciful in their anticipated
triumph. The letter, one of the noblest of Dante’s utterances, is a
landmark in the growth of the national idea in Italy; rulers and
peoples are admonished as members of one body; the good tidings
are announced to the nation as a whole; the writer’s Italian
citizenship is placed before his Florentine origin, when he subscribes
himself: “The humble Italian, Dante Alighieri, a Florentine unjustly
exiled.” It was in the bitter indignation caused by the Guelf
opposition, the alliance between Florence and King Robert, and the
doubt occasioned by the Emperor’s own delay in Lombardy, that
Dante from the Casentino wrote the terrible Letters vi. and vii., on
March 31st, 1311, to the Florentines, “the most wicked Florentines
within,” and on April 17th to Henry himself, “the most sacred
triumphant and only lord.” The former denounces the Florentines for
their rebellion, their “shrinking from the yoke of liberty,” their attempt
to make their civic life independent of that of Rome, and, in prophetic
fashion, warns them of their coming destruction at the hands of “the
prince who is the giver of the law.” In the latter, adopting the part of
Curio towards Caesar (which he himself condemns in the Inferno),
Dante urges the Emperor without further delay to turn his forces
upon Florence, who “sharpens the horns of rebellion against Rome
which made her in her own image and after her likeness.” The poet’s
attitude is that of the Hebrew prophets; his motive, the conviction
that his native city had adopted a line of policy opposed to the true
interests of Italy. These three letters are contained in the Vatican
MS.; Letters v. and vii. (of both of which early Italian translations are
extant) also in the S. Pantaleo MS., and there is a third (fifteenth
century) MS. of the letter to the Emperor.
Epistles VII.*, VII.** and VII.***.—These three letters are a
humble pendant to the three just considered. They are addressed to
Margaret of Brabant, the wife of the Emperor Henry, in the name of
the Countess of Battifolle (Gherardesca, daughter of Count Ugolino,
married to Guido di Simone of the Conti Guidi). They are in answer
to letters from the Empress, and, while containing mere expressions
of loyal devotion and aspirations for the triumph of the imperial
cause, their place in the Vatican MS. among the letters of Dante,
together with the close resemblance in style and phraseology with
the latter, has led to a general acceptance of the view that they were
written by the poet. They were written in the spring of 1311, the third
being dated from Poppi on May 18th.
Epistle VIII.—The letter to the Italian Cardinals, which is
mentioned by Villani, and echoed by Petrarch in his canzone on
Rome (“Spirto gentil che quelle membra reggi”), is found only in
Boccaccio’s autograph manuscript. It was written shortly after the
death of Clement V. (April 20, 1314), when the cardinals were
assembled in conclave at Carpentras; lamenting the desolation of
the sacred city, it exhorts them, “for the bride of Christ, for the seat of
the bride, which is Rome, for our Italy, and, to speak more fully, for
the whole estate of those on pilgrimage on earth,” to restore the
Apostolic See to its consecrated place. It is a noble protest of a
devout and learned layman against a corrupt and ignorant clergy, of
a Catholic and an Italian patriot against the papal desertion of Rome,
in which Dante stands forth as the new Jeremiah, renewing for the
sacred city of Christendom the lamentation of his Hebrew
predecessor for Jerusalem. The letter presents striking analogies
with the canto of the simonist popes (Inf. xix.), but is more moderate
in tone, as the poet is here less denouncing than attempting to
convert the cardinals to his point of view. There is extant a letter to
the French King from Cardinal Napoleone Orsini (whom Dante
admonishes by name in the epistle) with passages of a somewhat
similar kind; it is tempting to suppose that the cardinal had actually
received the exhortation and caught fire from the burning words of
his fellow Italian.
Epistle IX.—The occasion of the letter refusing the amnesty has
been already considered (chap. i.). It was probably written in the
latter part of May 1315. In the Boccaccian autograph (in which alone
it is found) it has no title; the traditional Amico florentino, “to a
Florentine friend,” is a later addition. It is practically the only example
of the poet’s personal correspondence that has been preserved.
Barbi has thrown grave doubts upon the identification of the person
to whom the letter is addressed with Teruccio di Manetto Donati, the
brother of Dante’s wife; the nephew mentioned may perhaps be
Andrea Poggi (cf. chap. i.) or, more probably, Niccolò Donati, the son
of Gemma’s brother Foresino. It is here that Dante calls himself the
preacher of justice, vir praedicans iustitiam, a claim which is the key
of the Commedia and may be traced from the canzone of the “Tre
donne.” Nor is it without significance that the closing words of the
letter, nec panis deficiet, “nor will bread fail me,” echo the same
chapter of Isaiah (li. 14) which inspired the canzone in which Dante
holds his exile as an honour.
Epistle X.—The Epistle to Can Grande stands apart from the
others. Although eight MSS. are now known, none are earlier than
the fifteenth century, and the two earliest contain no more than the
opening sections. Some of the early commentators—Pietro Alighieri,
Fra Guido da Pisa, and Boccaccio—were evidently acquainted with
it; it was first expressly quoted by Filippo Villani in 1391, and
published first in 1700, before any of Dante’s letters had seen the
light, excepting the unsatisfactory Italian version of the Epistle to
Henry of Luxemburg. If genuine, and its authenticity though much
disputed seems now almost certain, it was probably written in 1318
or early in 1319, apparently before the first Eclogue.
Beginning with language of enthusiastic praise and grateful
friendship, which recalls analogous passages in Canto xvii., the poet
prepares to pay back the benefits he has received with the
dedication of the Paradiso. So far (1-4), the epistolary form has been
maintained, and this is the only portion of the letter found in the
earlier MSS.; but now the writer assumes the office of a lecturer,
and, with a quotation from the Metaphysics of Aristotle, proceeds to
give an introduction to the Commedia and a commentary upon the
first canto of the third cantica. He distinguishes the literal and
allegorical meanings, defines the title of the whole (“The Comedy of
Dante Alighieri, Florentine by birth, not by character”) and of the part,
and explains the difference between comedy and tragedy from a
somewhat different point of view from that of the De Vulgari
Eloquentia (ii. 4). The subject of the Paradiso, in the literal sense, is
the state of the blessed after death; in the allegorical sense, man
according as by meriting he is subject to Justice rewarding. “The end
of the whole and of the part is to remove those living in this life from
the state of misery, and to lead them to the state of felicity” (Epist. x.
15). Dante emphasises the ethical aspect of the poem: “The whole
as well as the part was conceived, not for speculation, but with a
practical object” (x. 16). Then follows a minute scholastic and
mystical interpretation of the opening lines of the first canto of the
Paradiso in the literal sense, closing in an eloquent and very
beautiful summary of the ascent through the spheres of Paradise to
find true beatitude in the vision of the Divine Essence. Throughout
this part of the letter Dante, when touching upon the details of his
vision, always speaks of himself in the third person, evidently
following the example of St. Paul in the Second Epistle to the
Corinthians. He unmistakably implies that he has actually been the
recipient of some personal spiritual experience, which he is unable
adequately to relate. That passionate self-reproach, which sounds in
so many passages of the Divina Commedia, makes itself heard here
too. If the invidious do not believe in the power of the human intellect
so to transcend the measure of humanity, let them read the
examples cited from Scripture and the mystical treatises of Richard
of St. Victor, Bernard, Augustine. But, if the unworthiness of the
speaker makes them question such an elevation, let them see in
Daniel how Nebuchodonosor by divine inspiration had a vision
against sinners: “For He who ‘maketh His sun to rise on the evil and
on the good, and sendeth rain on the just and on the unjust,’
sometimes in mercy for their conversion, sometimes in wrath for their
punishment, reveals His glory, in greater or less measure, as He
wills, to those who live never so evily” (Epist. x. 28). This section of
the letter, for the student of mystical experience, is of the highest
significance.
4. The “Eclogae”
Belonging, like the tenth Epistle, to that closing period of Dante’s
life when he was engaged on the Paradiso, are two delightful
pastoral poems in Latin hexameters. Here, too, we owe much to the
piety of Boccaccio. The earliest and most authoritative of the five
manuscripts is again in his handwriting, in the Zibaldone
Boccaccesco (where the poems are accompanied by explanatory
notes), in the Laurentian Library.
Giovanni del Virgilio, a young lecturer and a poet, had written to
Dante from Bologna a letter in Latin verse, expressing his profound
admiration for the singer of the Commedia, but respectfully
remonstrating with him for writing in Italian, and suggesting some
stirring contemporary subjects as worthy matters for his muse: the
death of Henry VII., the battle of Montecatini, a victory of Can
Grande over the Paduans, the struggle by sea and land between
King Robert of Naples and the Visconti for the possession of Genoa.
The reference to this last event shows that the letter cannot have
been written before July 1318, while a passage towards the close
clearly indicates the early part of the following year. It further
contains a pressing invitation to come and take the laurel crown at
Bologna, or, at least, to answer the letter, “if it vex thee not, to have
read first the feeble numbers which the rash goose cackles to the
clear-voiced swan.”
Dante’s first Eclogue is the answer. Adopting the pastoral style, he
himself and his companion Dino Perini (whom Boccaccio afterwards
knew) appear as shepherds, Tityrus and Meliboeus, discussing the
invitation from Mopsus. It was probably written in the spring or early
summer of 1319. In a medley of generous praise and kindly banter,
Dante declines to visit Bologna, “that knows not the gods,” and still
hopes to receive the poet’s crown at Florence. When the Paradiso is
finished, then will it be time to think of ivy and laurel; and in the
meanwhile, to convert Mopsus from his errors with respect to
vernacular poetry, he will send him ten measures of milk fresh from
the best-loved ewe of all his flock—ten cantos from the Paradiso,
which evidently are not yet published, since the sheep is yet
unmilked.
Mopsus in his answer expresses the intense admiration with which
he and his fellow Arcadians have heard this song, and adopts the
same style. Condoling with Dante on his unjust exile, he foresees his
return home and reunion with Phyllis, who may perhaps be Gemma
or (as Carducci suggested) an impersonification of Florence. But, in
the meanwhile, pastoral pleasures and an enthusiastic welcome
await him at Bologna, if Iolas (Guido da Polenta) will let him go. A
reference to “Phrygian Muso” enables us to fix approximately the
date; towards the beginning of September, 1319, Albertino Mussato,
the Paduan poet and patriot, was at Bologna, endeavouring to get
aid from the Guelf communes for his native city against Can Grande.
Dante could hardly have with consistency accepted the invitation.
The writer of the notes on the Laurentian manuscript, whether
Boccaccio himself or another, commenting upon a poem sent by
Giovanni del Virgilio to Albertino Mussato, states that Dante delayed
a year before answering this Eclogue, and that his reply was
forwarded after his death by his son. His second Eclogue is in
narrative form, and professes to be no more than the report by the
writer of a conversation between Dante and his friends which is
overheard by Guido da Polenta. A new associate of the poet’s last
days is introduced to us: the shepherd Alphesiboeus, who is
identified with Fiducio de’ Milotti of Certaldo, a distinguished
physician resident at Ravenna. The tone is the same as that of the
other Eclogue. Ravenna becomes the pastures of Pelorus, while
Bologna is the Cyclops’ cave, to which Dante still refuses to go, for
fear of Polyphemus, whose atrocities in the past are recorded.[26]
And the crown expected now is, perhaps, no longer one which any
earthly city can give: “For this illustrious head already the Pruner is
hastening to award an everlasting garland.”
These two Eclogues are of priceless value. Nowhere else is such
a comparatively bright picture of Dante’s closing days given us. The
genuine and hearty laughter which greets Giovanni’s two letters, the
generous tone of the supreme singer towards the young scholar
poet, the kindly joking at the expense of Dino, make delightful
reading and show us quite another side of Dante’s character.
Giovanni’s first letter implies that the earlier parts of the Commedia
had not only been published, but had acquired a certain popularity.
From Dante’s first Eclogue it follows that, by 1319, both Inferno and
Purgatorio were completed, and that the Paradiso was in
preparation: “When the bodies that flow round the world, and they
that dwell among the stars, shall be shown forth in my song, even as
the lower realms, then shall I delight to crown my head with ivy and
with laurel.” And after this the passage in the second Eclogue,
written apparently in 1321, however we interpret it, has the same
pathos and sanctity as Petrarch’s note on the last line of his Triumph
of Eternity, or the abrupt ending of Shelley’s Triumph of Life:
Hoc illustre caput, cui iam frondator in alta
virgine perpetuas festinat cernere frondes.[27]
5. The “Quaestio de Aqua et Terra”

The Quaestio de Aqua et Terra—which purports to be a discourse
or lecture delivered by Dante in the church of Sant’ Elena at Verona
on January 20th, 1320—was first published in 1508 by an
Augustinian friar, Giovan Benedetto Moncetti. No manuscript of it is
known to exist, and there is no reference to the work or to the event
in any earlier writer, though Antonio Pucci (after the middle of the
fourteenth century) implies that Dante sought disputations of this
kind. In this work the poet—in accordance with the physical science
of his age—discusses the question of the relative position of the
element earth and the element water upon the surface of the globe.
The Quaestio was until recently regarded as a fabrication of the early
sixteenth century, but Moore in England and Vincenzo Biagi in Italy,
mainly on the internal evidence of the work itself, have convinced
many Dante scholars that it may be regarded with some probability
as authentic.
FOOTNOTES:
[19] In the recently discovered codex at Berlin—the earliest of
the four extant MSS.—the work is entitled Rectorica Dantis (“The
Rhetoric of Dante”), which would associate it with the similarly
named treatises of the masters of the ars dictandi, such as
Boncompagno da Signa, who wrote a Rhetorica novissima.
[20] This southern idiom (nostrum ydioma, i. 10)—from which
Dante apparently regards both classical Latin and the modern
romance languages derived—would be what we now call Vulgar
Latin; but he restricts the phrase vulgare latinum (or latium) to
Italian, which—when discussing the rival claims of the three
vernaculars to pre-eminence—he rightly recognises to be closest
to classical Latin.
[21] Equalium stantiarum sine responsorio ad unam sententiam
tragica coniugatio (ii. 8). The sine responsorio distinguishes the
true canzone, canzone distesa, from the ballata, canzone a ballo,
in which the ripresa of from two to four lines was repeated after
each stanza as well as sung as a prelude to the whole. Dante’s
example is his own Donne ch’avete intelletto d’amore, the poem
which began “le nove rime” (Purg. xxiv. 49-51). The tragica
coniugatio is most nearly realised in English poetry by the ode,
while the closest counterpart to the canzone with stanzas divisible
into metrical periods is offered by Spenser’s Epithalamion. The
sestina has been employed by English poets from the
Elizabethans to Swinburne and Rudyard Kipling.
[22] Cipolla showed that the matter of the first two books more
directly controverts the anti-imperialist and anti-Roman arguments
of the French political writers of the beginning of the fourteenth
century—writers like the Dominican, John of Paris. But these or
similar views were now being adduced by Robert of Naples and
supported by Clement V.
[23] These two ends are the two cities—the earthly and the
heavenly—of St. Augustine’s De Civitate Dei; but the earthly city,
blessedness of this life, is more significant for Dante than it was
for Augustine. Felicity in peace and freedom is in some sort man’s
right: Che è quello per che esso è nato (Conv. iv. 4).
[24] For the whole history of the Letters, the reader is referred
to Dr. Paget Toynbee’s introduction, Dantis Alagherii Epistolae,
Oxford, 1920.
[25] Torraca would assign it to 1311.
[26] Polyphemus, as Biscaro has shown, is most probably
Fulcieri da Calboli, the ferocious podestà of Florence in 1303,
who had been elected Captain of the People at Bologna for the
first six months of 1321 (his predecessor having died in office). Cf.
Ecl. ii. (iv.) 76-83 with Purg. xiv. 58-66. See Giornale storico della
letteratura italiana, lxxxi. p. 128. Others have taken the person
meant as Robert of Naples, or, with Ricci, a kinsman of Venedico
Caccianemico whom Dante had covered with infamy in Inf. xviii.
[27] “This illustrious head, for which the Pruner is already
hastening to select unwithering leaves from the noble laurel,” or
“to decree an everlasting garland in the divine justice,” according
to whether the Virgin is taken as Daphne or Astraea.
CHAPTER IV
THE “DIVINA COMMEDIA”
1. Introductory
Letter and Allegory.—The Divina Commedia is a vision and an
allegory. It is a vision of the world beyond the grave; it is an allegory,
based upon that vision, of the life and destiny of man, his need of
light and guidance, his duties to the temporal and spiritual powers, to
the Empire and the Church. In the literal sense, the subject is the
state of souls after death. In the allegorical sense, according to the
Epistle to Can Grande, the subject is “man as by freedom of will,
meriting and demeriting, he is subject to Justice rewarding or
punishing” (Epist. x. 11). There is, therefore, the distinction between
the essential Hell, Purgatory, Paradise of separated spirits—the lost
and the redeemed—after death; and the moral or spiritual Hell,
Purgatory, Paradise, of men still united to their bodies in this life,
using their free will for good or for evil; sinning, doing penance, living
virtuously. The Inferno represents the state of ignorance and vice;
the Purgatorio is the life of converted sinners, obeying Caesar and
reconciled to Peter, doing penance and striving God-wards; after the
state of felicity has been regained in the Earthly Paradise, the
Paradiso represents the ideal life of action and contemplation,
closing in an anticipation, here and now, of the Beatific Vision. The
whole poem is the mystical epic of the freedom of man’s will in time
and in eternity, the soul after conversion passing through the stages
of purification and illumination to the attainment of union and fruition.
It must be admitted that the allegorical interpretation of the
Commedia has frequently been carried to excess. This has led to a
reaction, represented now by Benedetto Croce, who would separate
the allegorical and didactic elements from the poetry, in which alone
the true value of the work consists. Such a tendency in its turn, if

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Drug Induced Liver Toxicity Minjun

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