The Role of Cytochrome P450IIE1 in Bioactivation of Acetaminophen in Diabetic and Acetone-Treated Mice

Abstract

Of a number of purified rabbit hepatic isozymes of P450, two isozymes exhibit appreciable activity in the bioactivation of acetaminophen (AP), isozymes P450IIE1 and P450IA2 (originally known as 3a and 4, respectively) [Morgan et al., 1983]. Using monoclonal antibodies to these isozymes Raucy and coworkers have determined the relative importance of these isozymes in human hepatic microsomal AP bioactivation. They found that P450IIE1 and P450IA2 were approximately equally responsible for AP bioactivation when human hepatic microsomes were incubated with 10 mM AP [Raucy et al., 1989]. In this study we have attempted to relate the role of P450IIE1 in AP bioactivation in murine hepatic microsomes to AP hepatotoxicity in the whole mouse. We have evaluated microsomal bioactivation in the presence and absence of an inhibitor of P450IIE1, dimethylsulfoxide (DMSO), and compared the effect of induction of P450IIE1 on hepatic microsomal AP bioactivation and on AP toxicity in the whole mouse.