Deck 7: Detoxication and Activation by Cells: Metabolism of the Original Toxicant

Question 1

Why is the benzoyl-CoA reductase a key enzyme in the difference between the metabolism of anaerobic bacteria and facultative anaerobes?

Answer 1

Anaerobes use this enzyme to metabolize aromatic hydrocarbons and this enzyme is inhibited by oxygen. Facultative anaerobes substitute an oxidase to yield the nonaromatic cis-dihydrodiols.

Question 2

What is the key reactant in the cytochrome P450 catalytic cycle and how is it formed?

Answer 2

It is the doubly reduced oxygen which may be represented by the short-lived perferryl oxygen intermediate or the phorphyrin radical species. This is produced by a two electron reduction of the heme iron CYPs by cytochrome P450 reductase and transfer to the bound oxygen. The binding of the substrate to the heme iron precedes these reaction steps and leads to an oxidized substrate and the other oxygen forming water.

Question 3

What reactions reduce toxicity by CYPs and which ones lead to less toxic products?

Answer 3

CYP1 and CYP2 isozymes produce toxic activated products of aryl hydrocarbons with epoxides (especially in the bay region of PAHs), quinoneimines, etc. Other CYPs (especially CYP3 and CYP6 isozymes) metabolized hydrophobic medications and make them more water soluble for removal by the kidney.

Question 4

Which inducers of CYPs lead to tolerance to medications while which ones cause more activation of procarcinogens?

Question 5

Which enzyme class metabolizes/oxidizes various amines depending on its isozyme?

Question 6

Which enzymes metabolize catecholamines and indolamines and their inhibition was used early on to help with depression, but also could lead to hypertension in cheese eaters?

Question 7

Which enzymes metabolize arachidonic acid and inhibition of these enzymes led to the development (therapeutic medications) and adverse effects (toxicity) of NSAIDS?

Question 8

Why does the metabolism of ethanol lead to a more toxic product to begin its conversion to a less toxic compound?

Question 9

Indicate the possible phase 2 metabolites that may indicate the formation of a less toxic intermediate versus one that indicates a reactive intermediate.