MECHANISMS OF

TOXICITY

FAR EASTERN UNIVERSITY – NICANOR REYES MEDICAL FOUNDATION

INSTITUTE OF MEDICINE - SCHOOL OF PHARMACY
 STAGES IN THE
DEVELOPMENT OF TOXICITY
1. DELIVERY : Site of Exposure to the
target
2. REACTION of the ultimate
toxicant with the target molecule
3. CELLULAR DYSFUNCTION and
RESULTANT TOXICITY
4. REPAIR AND DYSREPAIR

FAR EASTERN UNIVERSITY – NICANOR REYES MEDICAL FOUNDATION

INSTITUTE OF MEDICINE - SCHOOL OF PHARMACY
 STEP 1 – DELIVERY
PROCESSES
ABSORPTION PRESYSTEMIC
ELIMINATION
DISTRIBUTION TO DISTRIBUTION AWAY
TARGET FROM THE TARGET

REABSORPTION EXCRETION
TOXICATION DETOXICATION

FAR EASTERN UNIVERSITY – NICANOR REYES MEDICAL FOUNDATION

INSTITUTE OF MEDICINE - SCHOOL OF PHARMACY
 STEP 1 – DELIVERY
ABSORPTION PRESYSTEMIC ELIMINATION

§ Transfer of chemical from site of § Toxicants may be eliminated

exposure into systemic circulation during transfer from the site of
exposure to the systemic circulation
§ transporters or via diffusion
§ chemical absorption à GI
§ Factors that influence absorption mucosal cells à enterohepatic
1. Concentration
circulation à pulmonary circulation
2. Surface area of exposure àsystemic circulation
3. Characteristics of epithelial layer
4. Lipid-solubility § may contribute to injury of the
digestive mucosa, liver and lungs

FAR EASTERN UNIVERSITY – NICANOR REYES MEDICAL FOUNDATION

INSTITUTE OF MEDICINE - SCHOOL OF PHARMACY
 STEP 1 – DELIVERY
DISTRIBUTION TO … DISTRIBUTION AWAY …

§ Mechanisms :
1. Porosity of the Capillary
Endothelium
2. Specialized Transport across
the plasma membrane
3. Accumulation in Cell Organelles
4. Reversible Intracellular Binding
§ Mechanisms:
1. Binding to Plasma Proteins
2. Specialized Barriers
3. Distribution to storage sites
4. Association with Intracellular
Binding Proteins
5. Export from cells

FAR EASTERN UNIVERSITY – NICANOR REYES MEDICAL FOUNDATION

INSTITUTE OF MEDICINE - SCHOOL OF PHARMACY
 STEP 1 – DELIVERY
EXCRETION REABSORPTION

§ removal of xenobiotics from blood and § Filtered toxicants may re-enter the
their return to the external environment blood by diffusing through
§ EXCRETION - physical mechanism ; peritubular capillaries
BIOTRASFORMATION – chemical
mechanism for eliminating toxicant § facilitated by tubular fluid
reabsorption
§ Major organs : kidney and liver
§ Inefficient processes :
§ Factors :
§ Excretion from the mammary glands 1. Lipid solubility of chemical
§ Excretion in bile 2. Extent of ionization
§ Excretion into the intestinal lumen from
blood
FAR EASTERN UNIVERSITY – NICANOR REYES MEDICAL FOUNDATION
INSTITUTE OF MEDICINE - SCHOOL OF PHARMACY
 STEP 1 – DELIVERY
TOXICATION DETOXICATION

§ biotransformation to harmful § Biotransformations that eliminate

substances the ultimate toxicant or prevents its
formation
§ metabolic activation
§ Detoxication of toxicants:
§ Increased activity may be due to § with no Functional group: detoxicated in 2
phases
conversion into: § Nucleophiles : by conjugation
§ Electrophiles § Electrophiles: involves conjugation with
§ Free radicals glutathione; covalent binding to proteins
§ Nucleophiles § Free radicals : prevention of conversion to more
reactive compounds
§ Redox – active reactants § Protein toxins: inactivated by thioredoxin which
reduces the essential disulfide bond
FAR EASTERN UNIVERSITY – NICANOR REYES MEDICAL FOUNDATION
INSTITUTE OF MEDICINE - SCHOOL OF PHARMACY
 STEP 1 – DELIVERY
§Detoxication fails:
1. The toxicant overwhelms the detoxication processes
2. A reactive toxicant inactivates a detoxicating enzyme
3. Detoxication is reversed after transfer to other tissues
4. Harmful by-products are produced by the detoxication
processes

FAR EASTERN UNIVERSITY – NICANOR REYES MEDICAL FOUNDATION

INSTITUTE OF MEDICINE - SCHOOL OF PHARMACY
 STEP 2 – REACTION OF THE
ULTIMATE TOXICANT
Ø ATTRIBUTES OF TARGET MOLECULES
Ø All endogenous compounds are potentially targets for
toxicants
§ Nucleic acids, proteins and membranes
Ø To identify a target molecule as being responsible for
toxicity, the ultimate toxicant :
§ Reacts with the target and adversely affects its function
§ Reaches an effective concentration at the target site
§ Alters target in a way that is mechanistically related to the observed toxicity

FAR EASTERN UNIVERSITY – NICANOR REYES MEDICAL FOUNDATION

INSTITUTE OF MEDICINE - SCHOOL OF PHARMACY
 STEP 2 – REACTION OF THE
ULTIMATE TOXICANT
Ø TYPES OF REACTIONS
1. NON-COVALENT BINDING
• hydrophobic interactions, H bonding, and ionic bonding
• Reversible due to low bonding energy
2. COVALENT BINDING
• Irreversible, permanently alters endogenous molecules
• Covalent adduct formation is common with electrophilic toxicants
3. HYDROGEN ABSTRACTION
• Neutral free radicals can readily abstract H atoms from endogenous compounds, subsequently
converting those compounds into radicals
4. ELECTRON TRANSFER
• Exchange electrons to oxidize or reduce other molecules, leading to formation of harmful by-
products
5. ENZYMATIC REACTIONS
• Few toxins act enzymatically on specific target proteins

FAR EASTERN UNIVERSITY – NICANOR REYES MEDICAL FOUNDATION

INSTITUTE OF MEDICINE - SCHOOL OF PHARMACY
 STEP 2 – REACTION OF THE
ULTIMATE TOXICANT
Ø EFFECTS OF TOXICANTS ON TARGET MOLECULES
1. DYSFUNCTION
q Chemicals inhibit the function of target molecules by blocking NT receptors or ion
channels, inhibiting enzymes, and interfering with cytoskeleton dynamics

2. DESTRUCTION
q Toxicants alter primary structure of endogenous molecules by means of cross-
linking and fragmentation

3. NEOANTIGEN FORMATION
q Covalent binding of xenobiotics or their metabolites to proteins may evoke an
immune response

FAR EASTERN UNIVERSITY – NICANOR REYES MEDICAL FOUNDATION

INSTITUTE OF MEDICINE - SCHOOL OF PHARMACY
 STEP 3 – CELLULAR DYSFUNCTION
AND RESULTANT TOXICITIES

FAR EASTERN UNIVERSITY – NICANOR REYES MEDICAL FOUNDATION

INSTITUTE OF MEDICINE - SCHOOL OF PHARMACY
 STEP 4 – REPAIR OR DYSREPAIR
Ø MOLECULAR REPAIR
§ Repair of Proteins
§ Thiol groups are essential for the function of numerous proteins
§ Oxidation of protein thiols can be reversed by enzymatic reduction that is catalyzed by
thioredoxin and glutaredoxin
§ Once oxidized, the catalytic thiol groups are recycled by reduction with NADPH
§ Repair of Lipids
§ Peroxidized lipids are repaired by a complex process involving a series reductants,
glutathione peroxidase and glutathione reductase.
§ NADPH is needed to recycle the reductants that are oxidized in the process
§ Repair of DNA
§ Nuclear DNA is stable in part because it is packaged in a condensed form called chromatin
§ Mitochodrial DNA is not condensed and lacks efficient repair mechanisms
§ Specialized mechanisms:
§ Direct repair, Excision repair, Non-homologous end joining, Recombinational repair
FAR EASTERN UNIVERSITY – NICANOR REYES MEDICAL FOUNDATION
INSTITUTE OF MEDICINE - SCHOOL OF PHARMACY
 STEP 4 – REPAIR OR DYSREPAIR
Ø CELLULAR REPAIR
§Autophagy of Damaged Cell Organelles
§ Cells suffering mild injury may repair themselves by removing and degrading
damaged components, such as organelles and protein aggregates
§ Important in terminally differentiated cells such as neurons, cardiac monocytes and
skeletal monocytes because renewal by cell replication is not possible
§Regeneration of Damaged Axons
§ Macrophages remove debris by phagocytosis and produce cytokines and growth
factors which activate Schwann cells to proliferate and transdifferentiate from
myelinating mode into growth support mode.

FAR EASTERN UNIVERSITY – NICANOR REYES MEDICAL FOUNDATION

INSTITUTE OF MEDICINE - SCHOOL OF PHARMACY
 STEP 4 – REPAIR OR DYSREPAIR
Ø TISSUE REPAIR
§Apoptosis
§ An active deletion of damaged cells
§ Apoptosis initiated by cell injury can be regarded as tissue repair
§ A cell undergoing apoptosis shrinks as its nuclear and cytoplasmic materials condense, and
then breaks into membrane-bound fragments that are phagocytosed without inflammation
§Proliferation
§ Repair of injured tissues involves both regeneration of lost cells, extracellular matrix and
reintegration of the newly formed elements into tissues and organs
§Side reactions to tissue injury
§ Resident macrophages and endothelial cells activated by cell injury also produce
inflammation, altered production of acute-phase protein and generalized reactions such as
fever
FAR EASTERN UNIVERSITY – NICANOR REYES MEDICAL FOUNDATION
INSTITUTE OF MEDICINE - SCHOOL OF PHARMACY
 STEP 4 – REPAIR OR DYSREPAIR
Ø MECHANISMS OF ADAPTATION
Ø Adaptation – harm – induced capability of the organism for
increased tolerance to the harm itself
Ø It involves responses acting to preserve or regain the biological
homeostasis in the face of increased harm from noxious stimulus
Ø Adaptation of toxicity may result from biological changes causing
1. Diminished delivery of the toxicant to the target
2. Decreased sized or susceptibility of the target
3. Increased capacity of the organism to repair itself
4. Strengthened mechanisms to compensate the toxicant-inflicted dysfunction
Ø excessive exposure can overwhelm these protective responses
Ø toxicants may impair the adaptive process itself

FAR EASTERN UNIVERSITY – NICANOR REYES MEDICAL FOUNDATION

INSTITUTE OF MEDICINE - SCHOOL OF PHARMACY
 STEP 4 – REPAIR OR DYSREPAIR
Ø TOXICITY RESULTING FROM INAPPROPRIATE REPAIR AND ADAPTATION
§ TISSUE NECROSIS
§ Cell injury progresses toward cell necrosis if molecular repair mechanisms are inefficient
or the molecular damage is not really reversible
§ Tissue necrosis occurs because the injury overwhelms and disables repair mechanisms,
including repair of damaged molecules, elimination of damaged cells by apoptosis and
replacement of lost cells by cell division
§ FIBROSIS
§ A pathologic condition characterized by excessive deposition of an extracellular matrix of
abnormal composition and is a specific manifestation of dysrepair of chronically injured tissue
§ CARCINOGENESIS
§ Chemical carcinogenesis involves inappropriate function of various repair mechanisms
including:
§ Failure of DNA repair
§ Failure of apoptosis
§ Failure to terminate cell proliferation

FAR EASTERN UNIVERSITY – NICANOR REYES MEDICAL FOUNDATION

INSTITUTE OF MEDICINE - SCHOOL OF PHARMACY