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a
Stanley Ho Centre for Emerging Infectious Diseases, The Chinese University of Hong Kong, Hong Kong, China
b Tuberculosis and Chest Service, Department of Health, Hong Kong, China
I nappropriate oxidative stress (and nitrosative stress) generally results from an imbal-
ance in the production of reactive oxygen species (ROS) and reactive nitrogen species
(RNS), alongside their reduced elimination and/or the suboptimal response of antioxi-
dative defense (1, 2) (Table 1). Oxidative stress is exogenous or endogenous in origin.
Exogenous oxidative stress can be induced by drugs, and endogenous oxidative stress
is inherently associated with some conditions and diseases (1). Inappropriate oxidative
stress is harmful to the host and may result in organ injury (1, 2). Covering only first-line
antituberculosis drugs, this review addresses whether and how oxidative stress may
contribute to antituberculosis drug-induced hepatotoxicity, which has been a long-
standing concern in the treatment of tuberculosis (3, 4).
Accepted manuscript posted online 21 May
OXIDATIVE STRESS AND DRUG-INDUCED HEPATOTOXICITY 2018
The liver is an important organ with substantial vulnerability to the deleterious effects Citation Yew WW, Chang KC, Chan DP. 2018.
Oxidative stress and first-line antituberculosis
of oxidative stress (1, 2). Mitochondria, microsomes, and peroxisomes of hepatocytes are drug-induced hepatotoxicity. Antimicrob
associated with the production of ROS, which impact the regulation of signaling pathways, Agents Chemother 62:e02637-17. https://doi
including peroxisome proliferator-activated receptor alpha (PPAR␣) governing fatty acid .org/10.1128/AAC.02637-17.
oxidation, and mitogen-activated protein kinase (MAPK) and related stress-sensitive kinases Copyright © 2018 American Society for
Microbiology. All Rights Reserved.
associated with proapoptosis. Furthermore, in Kupffer cells, oxidative stress might induce
Address correspondence to Denise P. Chan,
the elaboration of cytokines, such as tumor necrosis factor alpha, that contribute to the denisechan@cuhk.edu.hk.
progression of tissue inflammation and cell apoptosis. In hepatic stellate cells, oxidative
August 2018 Volume 62 Issue 8 e02637-17 Antimicrobial Agents and Chemotherapy aac.asm.org 1
Minireview Antimicrobial Agents and Chemotherapy
TABLE 1 Some reactive oxygen species, reactive nitrogen species, and components of
antioxidative defense
Category Substance
Reactive oxygen species Hydroxyl ion (OH⫺)
Hydroxyl radical (·OH)
Peroxide (·O22⫺)
Hydrogen peroxide (H2O2)
Superoxide anion (·O2⫺)
Singlet oxygen (1O2)
stress-mediated lipid peroxidation can lead to increased collagen synthesis. Complex cross
talk between oxidative stress (nitrosative stress) and immune responses has been sug-
gested to play a critical role in the pathogenesis of liver injury (Fig. 1). In humans and other
mammalian species, a sophisticated antioxidative system to preserve redox homeostasis is
found in the liver (1). However, when perturbation of the homeostasis is to such a degree
that it culminates in overwhelming oxidative stress that challenges the liver of the host,
jeopardy of the organ status ensues due to damage to intracellular targets, notably lipids,
proteins, and DNA, and there is an adverse impact on key signaling pathways for the
FIG 1 A simplified representation of the pathogenesis of drug-induced hepatotoxicity. Oxidative stress and mitochondrial dysfunction
are important mechanisms contributing to drug-induced hepatotoxicity. Genetic polymorphisms associated with drug metabolism,
oxidative stress, and immune response interact in an intricate way, with conditions/diseases associated with oxidative stress per se,
leading to cellular inflammation, apoptosis, and necrosis, which manifest as histopathological changes of hepatotoxicity. The dashed
line indicates possible interaction between immunological response and oxidative stress.
FIG 2 Metabolism of isoniazid in the liver. Isoniazid is metabolized by acetylation to acetylhydrazine and
diacetylhydrazine. Acetylhydrazine can be hydrolyzed further to become isoniazid hydrazine, which also
results from the hydrolysis of isoniazid itself. Isoniazid hydrazine is toxic to hepatocytes, and so are the
more toxic reactive metabolites further derived from it through the activities of cytochrome P450
enzymes.
maintenance of optimal biological functions of the liver involved, and even other organs
(2). Some examples of drug-induced hepatotoxicity associated with oxidative stress are as
follows. It has been shown that acetaminophen-induced hepatotoxicity is related to its
metabolic derivative, N-acetyl-p-benzoquinone imine, which depletes glutathione (GSH)
from cellular storage and promotes protein adducts in mitochondria. Mitochondrial dys-
function and oxidative stress thus ensue, with subsequent activation of c-jun N-terminal
kinase (JNK) and ultimate induction of mitochondrial membrane permeability transition
(MPT). Apoptosis-inducing factor and endonuclease G are then released, leading to nuclear
patients with clinical liver disease. Studies of enzymatic and nonenzymatic systems in
addressing the pro-oxidant and antioxidant status in animal models and subjects with
chronic alcoholism have been performed, however, with somewhat disparate results
(2). As in diabetes mellitus, the shared pathogenetic basis of oxidative stress for organ
injury highlights the possible mechanism underlying disease-drug interaction when
patients with alcoholic liver disease receive antituberculosis treatment.
Chronic viral hepatitis and oxidative stress. The relative risk of developing
antituberculosis drug-induced hepatotoxicity among patients with chronic viral hepa-
titis is about 3- to 5-fold that of the general population (8, 10). Studies have also shown
that the severity of hepatotoxicity was related to the viral load at the time of initiating
antituberculosis therapy (46, 47). In the face of chronic viral hepatitis, the host immune
responses are largely responsible for the generation of ROS and RNS, as well as
mitochondrial dysfunction. It has also been shown that hepatitis C infection is associ-
ated with a greater production of ROS than other hepatitis viruses (48, 49). The level of
ROS was found to correlate with the likelihood of developing chronic hepatic disease,
namely, chronic hepatitis, cirrhosis, and hepatocellular carcinoma. ROS has also been
found to affect viral genome translation and induce viral genome heterogeneity. A
number of core viral proteins of hepatitis C virus are associated with oxidative stress.
Hepatitis C virus also affects enzymes, some of which pertain to antioxidant pathways.
The availability of much information notwithstanding, huge gaps in the knowledge still
exist regarding ROS scenarios in hepatitis C infection. Interestingly, steatosis is one
conspicuous histopathological feature in chronic liver disease due to hepatitis C
infection. It appears that both host and virus factors contribute to the development of
this liver pathology, which is probably caused by ROS/RNS-mediated disturbance in
lipid metabolism. Furthermore, there appears a link between chronic hepatitis C
infection and insulin resistance and diabetes mellitus (50, 51). Taken together, the
information underscores extremely important awareness regarding the enhanced pre-
disposition to hepatotoxicity incurred by chronic hepatitis C disease and antitubercu-
losis therapy. In chronic hepatitis B infection, there is also some evidence for the
occurrence of oxidative stress (52). As in chronic hepatitis C infection, sometimes the
studies regarding antioxidant status have yielded rather conflicting results in patients
with chronic hepatitis B infection (49, 52). This notwithstanding, great vigilance has to
stress (57, 58). In recent years, the pharmacogenomics knowledge base has been
accumulating (57–60). Table 2 depicts some important genes, apart from NAT2, CYP2E1,
and GST, which may be associated with isoniazid-induced hepatotoxicity. For truly
idiosyncratic drug-induced liver injury, it might be difficult to estimate the population-
attributable risk and clinically relevant absolute risk regarding these genetic polymor-
phisms. However, regarding some populations with risk factors for antituberculosis
drug-induced hepatotoxicity, further fathoming appears justified. In this connection, it
also appears that more research is warranted regarding the possible interaction be-
tween genetic polymorphisms associated with drug metabolism and oxidative stress, in
the generation of drug-induced liver injury. As an example, genetic variation of SOD2
has recently been found to be associated with alcoholic cirrhosis (61), and genetic
polymorphisms of SOD2 and cytochrome CYP 2E1 have been found to be associated
with nonalcoholic steatohepatitis (62).
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