Principles of Biochemical Toxicology

Question 1

Which circulatory Zone of the liver’s acinus is most prone to toxic damage?

Answer 1

Zone 3 of 1-3, due to poor blood supply compared to Zone 1. Zones closer to blood supply allow for better exchange of xenobiotics and for richer oxygen/nutrient supply.

Question 2

What are the key differences in enzymatic activity and energy sources between Zone 1 and Zone 3 hepatocytes? Why is this relevant to toxicological differences between these?

Answer 2

Zone 1 hepatocytes are more aerobic than Zone 3, relying on peroxidase and alcohol dehydrogenase. Zone 3 are more dependent on cytochrome P-450 enzymes and rely on lipid synthesis for energy reserves. The increased lipid synthesis and subsequent accumulation is a target of several hepatotoxins.

Question 3

What is the mechanism by which phalloidin elicits liver toxicity? What is the source of phalloidin?

Answer 3

Phalloidin causes ischemia through damage to cytoskeletal components of cells. This leads to a lack of oxygen, increased cellular calcium (due to disruption of actin filaments) and subsequent cytotoxic damage. Lack of blood flow leads to damage to sinusoids fo the liver.

Phalloidin is produced by the death cap mushroom.

Question 4

Hydrazine, tetracycline and ethanol are are all capable of causing what form of hepatotoxicity? How do their mechanisms differ for causing this outcome?

Answer 4

Fatty liver (Steatosis)

Tetracycline inhibits protein synthesis, thereby reducing the production of apoprotein (lipid acceptor protein). Hydrazine will induce diglyceride production, and also depletes ATP thereby affecting protein synthesis. Ethanol induces lipid synthesis and suppresses lipid catabolism.

Question 5

Allyl alcohol is metabolized into what product in the liver? Which Zone does this occur in?

Answer 5

Allyl alcohol is converted into acrolein in Zone 1 of the liver via alcohol dehydrogenase.