ALCOHOL-MEDIATED INCREASES IN ACETAMINOPHEN HEPATOTOXICITY - ROLE OF CYP2E AND CYP3A

This commentary focuses on the roles of CYP3A and CYP2E in alcohol-med iated increases in acetaminophen hepatotoxicity. CYP2E has been consid ered to be the main form of P450 responsible for such toxicity in anim als and humans. However, CYP3A, which is also induced by alcohol, has been shown to have a greater affinity for acetaminophen than CYP2E. Pr evious experiments implicating CYP2E in alcohol-mediated increases in acetaminophen hepatotoxicity have used inhibitors of this form of P450 that are now proving to be non-specific. Triacetyloleandomycin (TAO) is a potent inhibitor of CYP3A that maintains specificity in vitro ove r a large concentration range. In rats treated with ethanol or the com bination of ethanol and isopentanol, the major higher chain alcohol in alcoholic beverages, TAO protects animals from increases in acetamino phen hepatotoxicity, suggesting a major role of CYP3A. CYP2E may not h ave a major role due to the rapid loss of induced Levels in the absenc e of continued exposure to ethanol. Knockout mice, which are being use d to define the role of particular proteins in biological responses, h ave been developed for CYP2E1 and CYP1A2 but not CYP3A. Cyp2el(-/-) an al Cyp1a2(-/-) mice are more resistant to acetaminophen hepatotoxicity than wild-type strains, even though the amounts of the other forms of P450s are unaltered in the liver. These findings suggest that the rel ative amounts of P450s and not just kinetic characteristics determine their role in acetaminophen hepatotoxicity. The clinical implications of the findings that CYP3A can have a major role in acetaminophen-medi ated hepatotoxicity are discussed. (C) 1998 Elsevier Science Inc.