Evaluation of hepatic cytochrome P4502E1 in the species-dependent bioactivation of 4-vinylcyclohexene

4-Vinyl-1-cyclohexene (VCH), is converted by multiple forms of cytochrome P 450 (CYP) to two monoepoxides (4-vinyl-1-cyclohexene 1,2-epoxide [VCH-1,2-e poxide], 4-vinyl-1-cyclohexene 7,8-epoxide [VCH-7,8-epoxide]). and 4-vinyl- 1-cyclohexene diepoxide (VCD). A greater degree of formation of these epoxi des by female B6C3F(1) mice as compared to Fischer 344 rats correlates with the ovarian toxicity observed only in the mice. Understanding which isofor ms of CYP are involved in VCH bioactivation will better explain the species -dependent ovotoxicity of VCH. Present studies focus on the role of CYP2E1, as this isoform is responsible for the bioactivation of several structural ly related small molecular weight compounds, including 1,3-butadiene. Hepat ic microsomes prepared from either mice or rats pretreated with the CYP ind ucer acetone demonstrated 2-fold increases in the formation of VCH-1,2-epox ide. However. incubations with microsomes from cyp2el-deficient mice compar ed to those from wild type mice revealed no differences in the rates of bio activation of VCH to the monoepoxides. Since repeated exposure to VCH is re quired for VCH-induced ovotoxicity, rodents were dosed with VCH for 5 or 10 d to observe effects on the hepatic concentration of CYP2E1 and/or associat ed activities. VCH pretreatment failed to increase the concentration of CYP 2E1 or CYP2E1 activity in either species, as measured by immunoblotting ana lysis and p-nitrophenol hydroxylation. Based on these data, it is concluded that CYP2E1 does not play a role in the species differences between mice a nd rats in the bioactivation of VCH following repeated exposure to VCH. Oth er isoforms, such as those in CYP2A and CYP2B subfamilies, are likely invol ved in VCH bioactivation. (C) 2001 Elsevier Science Inc. All rights reserve d.