| Abstract
| - The stereochemical course of the biotransformation of 4-vinylcyclohexene (VCH, 1) by livermicrosomes from male and female control and induced rats and purified rat P450 2B1 and2E1 has been determined. The epoxidation of 1, catalyzed by male microsomes, occurs on boththe endo- and exocyclic double bond to give four isomeric epoxides, cis-4-vinylcyclohexene 1,2-epoxide (2), trans-4-vinylcyclohexene 1,2-epoxide (3), (4R*,7S*)-4-vinylcyclohexene 7,8-epoxide(4), and (4R*,7R*)-4-vinylcyclohexene 7,8-epoxide (5). On the other hand, microsomes fromfemale rats catalyzed primarily the endocyclic epoxidation. The stereoselectivity of this processwas strongly dependent on gender and P450 induction. Only the phenobarbital and pyrazole,at lower levels, were able to enhance the epoxidation of 1 and mostly on the endocyclic doublebond. Also, P450 2E1 and 2B1 in a reconstituted system were able to perform the epoxidationof 1 primarily on its endocyclic double bond. The metabolites, cis- and trans-4-vinylcyclohexene1,2-epoxide (2 and 3, respectively) and the isomeric 4-vinylcyclohexene 7,8-epoxides (4 and 5),were rapidly biotransformed into the corresponding vicinal diols by mEH-catalyzed hydrolysis.The reaction of the endocyclic epoxides occurred with good substrate diastereo- and enantioselectivity favoring the hydrolysis of epoxides (1S,2R,4S)-3 and (1R,2S,4S)-2 to give, before50% conversion, selectively (1R,2R,4S)-diol (6). At variance, the hydrolysis of the exocyclicepoxides was characterized by a high level of substrate enantioselection associated with a verylow, if any, level of substrate diastereoselection, the two epoxides, (4R,7S)-4 and (4R,7R)-5,being hydrolyzed practically with the same rate. On the basis of the major resistance to mEHhydrolysis, the endocyclic epoxides, (1R,2S,4R)-3 and (1S,2R,4R)-2, are expected to be furtheroxidized, in a stereochemical manner, to the specific mutagenic diepoxides which are thoughtto play a crucial role in VCH ovotoxicity. Thus, VCH ovotoxicity may be markedly affected bythe reactivity of the diepoxidic stereoisomers formed and detoxicated.
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