Hepatotoxicity Flashcards
ALT meaning
Alanine transferase
AST meaning
Aspartate aminotransferase
ALP meaning
Alkaline phosphatase
Toxicants for fatty liver disease
- 2-nitropropane, aflatoxin, dioxin, atrazine,
- carbon tetrachloride, chlordecone, chloroform
- lead, arsenic,
- methylmercury,
- N,N-dimethylformamide, nitrobenzene, nitrotoluene,
- paraquat, petrochemicals, polychlorinated biphenyls (PCBs),
- tetrachloroethylene, trichloroethane, trichloroethylene, thallium,
vinyl chloride
Morphologic changes in liver necrosis
- Cytoplasmic oedema
- dilation of the endoplasmic reticulum,
- accumulation of triglycerides,
- swelling of mitochondria with disruption of cristae
- dissolution of organelles and nucleus.
Biological events that cause morphological changes in liver necrosis
- binding of reactive metabolites to proteins and unsaturated lipids (inducing lipid peroxidation and subsequent membrane disruption)
- disturbance of cellular Ca2+ homeostasis,
- interference with metabolic pathways,
- shifts in Na+ and K+ balance
- inhibition of protein synthesis.
Examples of substances implicated in liver necrosis include:
- acetaminophen
- arsenic,
- carbon tetrachloride and other halogenated aliphatic hydrocarbons
- haloaromatic compounds
- nitroaromatic compounds
- yellow phosphorus
Apoptosis can be induced by
Xenobiotics
Oxidative stress
Anoxia
Radiation
Apoptosis can be distinguished from necrosis by…
…morphologic criteria, using either light or electron microscopy.
Effects of cholestasis
Retention of bile salts as well as bilirubin accumulation, which leads to jaundice.
Other mechanisms include changes in membranes permeability of either hepatocytes or biliary canaliculi.
Toxicants that cause cholestasis include
- beryllium,
- copper
- di(2-ethylhexyl) phthalate,
- methylenedianiline,
- paraquat,
- toxic rapeseed oil
- drugs such as chlorpromazine, imipramine, carbarsone
Effects of cirrhosis
Severe restriction in:
- liver blood flow
- metabolic functions
- detoxification processes
Toxicant causes of cirrhosis
- Arsenic
- CCl4
- PCBs
- Vinyl chloride
- trichloroethane
- trichloroethylene
- trinitrotoluene
Implicated toxicants for hepatitis include:
urethane,
vinyl chloride,
trichloroethylene
Trinitrotoluene
Thorotrast,
Effects of oxidative stress in liver
Several liver diseases, including alcoholic liver, metal storage, and cholestatic liver diseases, have been associated with oxidative stress.
How are prooxidants formed in the liver?
- Reactive oxygen radicals such as superoxide, hydrogen peroxide, and hydroxyl ions can be formed as by-products of mitochondrial electron transport.
- Monooxygenases and peroxisomes also produce reactive species.
Mode of action of prooxidants in oxidative stress
Reactive oxygen species interact with biological macromolecules such as DNA and proteins or with lipids to induce lesions or damage.
Chemicals implicated in liver carcinogenesis and their sources include
Beryllium - Coal fired power plants, airborne particles of Be matter
Copper - Contaminated food and water, Wilson’s disease
Thorotrast - Radiocontrast agents
Polychlorinated biphenyls (PCBs) - Plastic, Dyes, Pigments
Aflatoxin B1 - Food contaminated with fungus, like groundnut, tree nuts
Dimethylbenzanthracene - Cancer research lab
Hepatotoxic mechanisms
- inhibition of enzymes,
- depletion of cofactors,
- depletion of energy (ATP) stores,
- interaction with receptors, and
- alteration of cell membranes
- enzyme induction
Example of enzyme inducer
phenobarbital and 3-methylcholanthrene
Inhibitors of cytochrome P450
SKF-525A and piperonyl butoxide.
CCl4 MOA
- Induces oxidative damage, inflammation, fatty acid degeneration, fibrosis
- Induces hypomethylated ribosomal RNA, inhibiting protein synthesis.
- Affects hepatocellular calcium homeostasis
Bromobenzene MOA
Relatively inert, but it is activated by metabolism to reactive bromobenzene-3,4-epoxide by CYP450
Binds covalently to macromolecules and works with oxidative stress and lipid peroxidation to cause centrilobular hepatocyte necrosis
Acetaminophen MOA
Forms active metabolite, N-acetyl-p-benzoquinone imine (NAPQI) which depletes cellular glutathione and forms protein adducts on mitochondrial proteins. This elevates level of free radicals like superoxide. Hi
Ethanol MOA
Hepatotoxic through redox changes produced by NADH generated in its oxidation via alcohol dehydrogenase pathway. This affects metabolism of macromolecules like lipids, carbs and proteins.
- Induces CYP450 enzyme that activates xenobiotics to toxic radicals. Induction also causes energy wastage as increased acetaldehyde production.
Acetaldehyde effects
- Forms protein adducts and causes injury, increasing antibody production, enzyme inactivation, decreased DNA repair
- Glutathione depletion
- Lipid peroxidation
- Hepatic collagen synthesis, leading to fibrosis
