title: Stereochemical aspects in the 4-vinylcyclohexene biotransformation with rat liver microsomes and purified p450s. monoepoxides and diols.
abstract: The stereochemical course of the biotransformation of 4-vinylcyclohexene (VCH, 1) by liver microsomes from male and female control and induced rats and purified rat P450 2B1 and 2E1 has been determined. The epoxidation of 1, catalyzed by male microsomes, occurs on both the 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 from female rats catalyzed primarily the endocyclic epoxidation. The stereoselectivity of this process was 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 double bond. Also, P450 2E1 and 2B1 in a reconstituted system were able to perform the epoxidation of 1 primarily on its endocyclic double bond. The metabolites, cis- and trans-4-vinylcyclohexene 1,2-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, before 50% conversion, selectively (1R,2R,4S)-diol (6). At variance, the hydrolysis of the exocyclic epoxides was characterized by a high level of substrate enantioselection associated with a very low, 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 mEH hydrolysis, the endocyclic epoxides, (1R,2S,4R)-3 and (1S,2R,4R)-2, are expected to be further oxidized, in a stereochemical manner, to the specific mutagenic diepoxides which are thought to play a crucial role in VCH ovotoxicity. Thus, VCH ovotoxicity may be markedly affected by the reactivity of the diepoxidic stereoisomers formed and detoxicated.
authors.affiliation: Dipartimento di Chimica Bioorganica e Biofarmacia, Università di Pisa, via Bonanno 33, 56126 Pisa, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Chiappe
authors.forename: A
authors.initials: A
authors.lastname: De Rubertis
authors.forename: M
authors.initials: M
authors.lastname: De Carlo
authors.forename: G
authors.initials: G
authors.lastname: Amato
authors.forename: P G
authors.initials: PG
authors.lastname: Gervasi
mesh_terms: D000818:Animals; D001711:Biotransformation / Q000502:physiology; D003510:Cyclohexanes / Q000737:chemistry / Q000378:metabolism*; D053138:Cyclohexenes; D019362:Cytochrome P-450 CYP2B1 / Q000378:metabolism*; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism*; D004851:Epoxide Hydrolases / Q000378:metabolism; D004852:Epoxy Compounds / Q000737:chemistry / Q000378:metabolism; D005260:Female; D006868:Hydrolysis; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D009153:Mutagens / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D014753:Vinyl Compounds / Q000737:chemistry / Q000378:metabolism
chemical_list: D003510:Cyclohexanes; D053138:Cyclohexenes; D004852:Epoxy Compounds; D009153:Mutagens; D014753:Vinyl Compounds; C013733:4-vinylcyclohexene; C118009:1,2-epoxy-4-vinylcyclohexane; C012606:4-vinyl-1-cyclohexene dioxide; D019392:Cytochrome P-450 CYP2E1; D019362:Cytochrome P-450 CYP2B1; D004851:Epoxide Hydrolases