Loss of CYP2E1 and CYP1A2 activity as a function of acetaminophen dose: relation to toxicity.
The effect of acetaminophen (APAP) dose on the cytochrome P450s responsible for its bioactivation was examined in control mice and mice treated with acetone to induce CYP2E1, or beta-napthaflavone to induce CYP1A2. In non-induced mice, 150 mg/kg APAP caused minimal hepatotoxicity and loss of CYP2E1- but not CYP1A2-dependent activity. In contrast, 400 mg/kg APAP was hepatotoxic and diminished both CYP2E1 and CYP1A2 activities. In acetone-pretreated mice, the 150 and 400 mg/kg APAP doses caused similar depletion of CYP2E1 activity and similar levels of covalent binding of APAP to liver proteins. In beta-napthaflavone-pretreated mice, CYP1A2 activity was decreased only by the high dose of APAP, and covalent binding was > 2-fold higher at the high APAP dose. The data indicate CYP2E1 is important in the bioactivation of APAP at the low dose with little additional contribution at the high dose, whereas CYP1A2 contributes more to the bioactivation and toxicity APAP at high doses.
Snawder
J E
JE
Division of Biochemical Toxicology, FDA, Jefferson, AR 72079.
Roe
A L
AL
Benson
R W
RW
Roberts
D W
DW
D000082:Acetaminophen / Q000633:toxicity*; D000096:Acetone / Q000494:pharmacology; D000818:Animals; D001571:Benzoflavones / Q000494:pharmacology; D019388:Cytochrome P-450 CYP1A2; D019392:Cytochrome P-450 CYP2E1; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000473:pathology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008862:Microsomes, Liver / Q000201:enzymology*; D010088:Oxidoreductases / Q000096:biosynthesis / Q000378:metabolism*; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis / Q000378:metabolism*; D013997:Time Factors; D019324:beta-Naphthoflavone
D001571:Benzoflavones; D000096:Acetone; D000082:Acetaminophen; D019324:beta-Naphthoflavone; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D019392:Cytochrome P-450 CYP2E1; D019388:Cytochrome P-450 CYP1A2; D010089:Oxidoreductases, N-Demethylating