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PHA 315 > Hepatotoxicity > Flashcards

Hepatotoxicity Flashcards

1
Q

ALT meaning

A

Alanine transferase

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2
Q

AST meaning

A

Aspartate aminotransferase

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3
Q

ALP meaning

A

Alkaline phosphatase

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4
Q

Toxicants for fatty liver disease

A
  • 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
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5
Q

Morphologic changes in liver necrosis

A
  • Cytoplasmic oedema
  • dilation of the endoplasmic reticulum,
  • accumulation of triglycerides,
  • swelling of mitochondria with disruption of cristae
  • dissolution of organelles and nucleus.
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6
Q

Biological events that cause morphological changes in liver necrosis

A
  • 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.
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7
Q

Examples of substances implicated in liver necrosis include:

A
  • acetaminophen
  • arsenic,
  • carbon tetrachloride and other halogenated aliphatic hydrocarbons
  • haloaromatic compounds
  • nitroaromatic compounds
  • yellow phosphorus
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8
Q

Apoptosis can be induced by

A

Xenobiotics
Oxidative stress
Anoxia
Radiation

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9
Q

Apoptosis can be distinguished from necrosis by…

A

…morphologic criteria, using either light or electron microscopy.

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10
Q

Effects of cholestasis

A

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.

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11
Q

Toxicants that cause cholestasis include

A
  • beryllium,
  • copper
  • di(2-ethylhexyl) phthalate,
  • methylenedianiline,
  • paraquat,
  • toxic rapeseed oil
  • drugs such as chlorpromazine, imipramine, carbarsone
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12
Q

Effects of cirrhosis

A

Severe restriction in:
- liver blood flow
- metabolic functions
- detoxification processes

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13
Q

Toxicant causes of cirrhosis

A
  • Arsenic
  • CCl4
  • PCBs
  • Vinyl chloride
  • trichloroethane
  • trichloroethylene
  • trinitrotoluene
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14
Q

Implicated toxicants for hepatitis include:

A

urethane,
vinyl chloride,
trichloroethylene
Trinitrotoluene
Thorotrast,

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15
Q

Effects of oxidative stress in liver

A

Several liver diseases, including alcoholic liver, metal storage, and cholestatic liver diseases, have been associated with oxidative stress.

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16
Q

How are prooxidants formed in the liver?

A
  • 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.
17
Q

Mode of action of prooxidants in oxidative stress

A

Reactive oxygen species interact with biological macromolecules such as DNA and proteins or with lipids to induce lesions or damage.

18
Q

Chemicals implicated in liver carcinogenesis and their sources include

A

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

19
Q

Hepatotoxic mechanisms

A
  • inhibition of enzymes,
  • depletion of cofactors,
  • depletion of energy (ATP) stores,
  • interaction with receptors, and
  • alteration of cell membranes
  • enzyme induction
20
Q

Example of enzyme inducer

A

phenobarbital and 3-methylcholanthrene

21
Q

Inhibitors of cytochrome P450

A

SKF-525A and piperonyl butoxide.

22
Q

CCl4 MOA

A
  • Induces oxidative damage, inflammation, fatty acid degeneration, fibrosis
  • Induces hypomethylated ribosomal RNA, inhibiting protein synthesis.
  • Affects hepatocellular calcium homeostasis
23
Q

Bromobenzene MOA

A

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

24
Q

Acetaminophen MOA

A

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

25
Q

Ethanol MOA

A

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.
26
Q

Acetaldehyde effects

A
  • Forms protein adducts and causes injury, increasing antibody production, enzyme inactivation, decreased DNA repair
  • Glutathione depletion
  • Lipid peroxidation
  • Hepatic collagen synthesis, leading to fibrosis

PHA 315 (6 decks)

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