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 P450 (CYP) to two monoepoxides (4-vinyl-1-cyclohexene 1,2-epoxide [VCH-1,2-epoxide], 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 epoxides by female B6C3F1 mice as compared to Fischer 344 rats correlates with the ovarian toxicity observed only in the mice. Understanding which isoforms 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 structurally related small molecular weight compounds, including 1,3-butadiene. Hepatic microsomes prepared from either mice or rats pretreated with the CYP inducer acetone demonstrated 2-fold increases in the formation of VCH-1,2-epoxide. However, incubations with microsomes from cyp2e1-deficient mice compared to those from wild type mice revealed no differences in the rates of bioactivation of VCH to the monoepoxides. Since repeated exposure to VCH is required 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 associated activities. VCH pretreatment failed to increase the concentration of CYP2E1 or CYP2E1 activity in either species, as measured by immunoblotting analysis and p-nitrophenol hydroxylation. Based on these data, it is concluded that CYP2E1 does not play a role in the species differences between mice and rats in the bioactivation of VCH following repeated exposure to VCH. Other isoforms, such as those in CYP2A and CYP2B subfamilies, are likely involved in VCH bioactivation.
Fontaine
S M
SM
Dept. of Pharmacology and Toxicology, Center for Toxicology, The University of Arizona, Tucson 85721-0207, USA.
Hoyer
P B
PB
Sipes
I G
IG
D000818:Animals; D001711:Biotransformation; D003510:Cyclohexanes / Q000493:pharmacokinetics*; D053138:Cyclohexenes; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D004852:Epoxy Compounds / Q000378:metabolism; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000201:enzymology*; D051381:Rats; D011916:Rats, Inbred F344
D003510:Cyclohexanes; D053138:Cyclohexenes; D004852:Epoxy Compounds; C013733:4-vinylcyclohexene; D019392:Cytochrome P-450 CYP2E1