Stereochemical aspects of vinylcyclohexene bioactivation in rodent hepatic microsomes and purified human cytochrome P450 enzyme systems.
The racemic mixture of 4-vinylcyclohexene (VCH) forms ovotoxic epoxides [VCH-1,2-epoxide, VCH-7,8-epoxide, and vinylcyclohexene diepoxide (VCD)] by cytochrome P450 (CYP) in B6C3F(1) female mice. These epoxides deplete primordial and primary follicles. The current studies compared in vitro epoxidation of (R)-VCH with that of (S)-VCH in hepatic microsomes prepared from adult female B6C3F(1) mice and Fischer 344 rats. Bioactivation of VCH in the rat was significantly less compared with that in the mouse. (R)-VCH formed significantly more VCH-1,2-epoxide as compared with (S)-VCH in both species, and less VCH-7,8-epoxide in the mouse. Neither of the enantiomers formed detectable amounts of VCD in the mouse or rat. Hepatic microsomes prepared from mice and rats pretreated with CYP-inducing agents (phenobarbital and acetone) were also incubated with (R)-VCH or (S)-VCH. Although monoepoxide formation was not increased enantioselectively in the mouse, VCD was formed preferentially from (R)-VCH as compared with (S)-VCH. Pretreatment with VCH resulted in nonstereoselective increases in both monoepoxide and diepoxide formation. In the rat, these pretreatments resulted in nonstereoselective increases in monoepoxide formation, but VCD formation was not detectable. Incubations with human CYP2E1 enzyme revealed that (R)-VCH formed significantly more VCH-1,2-epoxide and less VCH-7,8-epoxide than (S)-VCH. Human CYP2A6 was limited in its ability to form epoxides from either enantiomer of VCH. Human CYP2B6 preferentially formed VCH-7,8-epoxide compared with VCH-1,2-epoxide, and to a greater extent from (R)-VCH than from (S)-VCH. These results demonstrate regioselectivity and enantioselectivity in the bioactivation of VCH in rodent hepatic microsomes as well as in expressed human CYP enzymes.
Fontaine
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Department of Pharmacology and Toxicology, The University of Arizona, P.O. Box 210207, Tucson, AZ, USA.
Mash
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Hoyer
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Sipes
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D000818:Animals; D001711:Biotransformation; D003510:Cyclohexanes / Q000378:metabolism / Q000493:pharmacokinetics*; D053138:Cyclohexenes; D003577:Cytochrome P-450 Enzyme System / Q000302:isolation & purification / Q000378:metabolism*; D004852:Epoxy Compounds / Q000378:metabolism / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000302:isolation & purification / Q000378:metabolism; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D010084:Oxidation-Reduction; D051381:Rats; D011916:Rats, Inbred F344; D013237:Stereoisomerism
D003510:Cyclohexanes; D053138:Cyclohexenes; D004852:Epoxy Compounds; D007527:Isoenzymes; C013733:4-vinylcyclohexene; D003577:Cytochrome P-450 Enzyme System