The stereochemical course of the biotransformation of 1,2-monoepoxides of 4-vinyleyclohexene (2 and 3) by liver microsomes from control and induced rats and by purified P4502B1 and P4502E1 has been determined. The epoxidation of monoepoxides cis-4-vinylcyclohexene 1,2-epoxide (2) and trans-4-vinyleyclohexene 1,2-epoxide (3) gives the corresponding eight isomeric diepoxides cis-4-vinylcyclohexene diepoxide (9) and trans-4-vinyleyclohexene diepoxide (10). The stereoselectivity of this process is affected by P450 induction. Phenobarbital is able to enhance the yield of epoxidation to give preferentially diepoxide (1R,2S,4R,7R)-trans-10b. This enantiomer is also formed as nearly the sole product by P450-catalyzed epoxidation of (1R,2S,4R)-trans-3b, the monoepoxide that, as a consequence of the selective formation from 4-vinyleyclohexene and/or reduced elimination by epoxide hydrolase, tends to accumulate in rat. Also, the P4502B1 but not 2E1, in a reconstituted system, is able to perform the epoxidation of (1R,2S,4R)-trans-3b to produce selectively the same diepoxide. Diepoxides cis-9 and trans-10 are biotransformed by mEH catalyzed hydrolysis. Although the hydrolysis of diepoxides 9 is characterized by a lower substrate enantioselection, the reaction of diepoxides 10 occurs with a good substrate enantioselectivity favoring the hydrolysis of the epoxides (1R,2S,4R,7S)-trans-10b and (1S,2R,4S,7S)-trans-10a. Diepoxide (1R,2S,4R,7R)-trans-10b is therefore the isomer primarily formed by P450-catalyzed oxidation of monoepoxide trans-3, and it is also the compound showing the lower propensity to undergo mEH-catalyzed hydrolysis. On the basis of this result, the ovotoxicity of 4-vinylcyclohexene is expected to be due to the stereoisomer diepoxide (1R,2S,411,711)-trans-10b, whose biological reactivity, via cross-linking, may be strongly different to the other isomer diepoxides, being dependent by its specific conformation.
Stereochemical aspects in the 4-vinylcyclohexene biotransformation with rat liver microsomes and purified cytochrome p450s: Diepoxide formation and hydrolysis
CHIAPPE, CINZIA;
2003-01-01
Abstract
The stereochemical course of the biotransformation of 1,2-monoepoxides of 4-vinyleyclohexene (2 and 3) by liver microsomes from control and induced rats and by purified P4502B1 and P4502E1 has been determined. The epoxidation of monoepoxides cis-4-vinylcyclohexene 1,2-epoxide (2) and trans-4-vinyleyclohexene 1,2-epoxide (3) gives the corresponding eight isomeric diepoxides cis-4-vinylcyclohexene diepoxide (9) and trans-4-vinyleyclohexene diepoxide (10). The stereoselectivity of this process is affected by P450 induction. Phenobarbital is able to enhance the yield of epoxidation to give preferentially diepoxide (1R,2S,4R,7R)-trans-10b. This enantiomer is also formed as nearly the sole product by P450-catalyzed epoxidation of (1R,2S,4R)-trans-3b, the monoepoxide that, as a consequence of the selective formation from 4-vinyleyclohexene and/or reduced elimination by epoxide hydrolase, tends to accumulate in rat. Also, the P4502B1 but not 2E1, in a reconstituted system, is able to perform the epoxidation of (1R,2S,4R)-trans-3b to produce selectively the same diepoxide. Diepoxides cis-9 and trans-10 are biotransformed by mEH catalyzed hydrolysis. Although the hydrolysis of diepoxides 9 is characterized by a lower substrate enantioselection, the reaction of diepoxides 10 occurs with a good substrate enantioselectivity favoring the hydrolysis of the epoxides (1R,2S,4R,7S)-trans-10b and (1S,2R,4S,7S)-trans-10a. Diepoxide (1R,2S,4R,7R)-trans-10b is therefore the isomer primarily formed by P450-catalyzed oxidation of monoepoxide trans-3, and it is also the compound showing the lower propensity to undergo mEH-catalyzed hydrolysis. On the basis of this result, the ovotoxicity of 4-vinylcyclohexene is expected to be due to the stereoisomer diepoxide (1R,2S,411,711)-trans-10b, whose biological reactivity, via cross-linking, may be strongly different to the other isomer diepoxides, being dependent by its specific conformation.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
