Sm. Fontaine et al., Evaluation of hepatic cytochrome P4502E1 in the species-dependent bioactivation of 4-vinylcyclohexene, LIFE SCI, 69(8), 2001, pp. 923-934
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.