Stereochemical course of the biotransformation of isoprene monoepoxides and of the corresponding diols with liver microsomes from control and inducedrats

The stereochemical course of the biotransformation of isoprene by liver enz ymes from control and induced rats has been determined. Between the two pri marily formed metabolites, 2-methyl-2-vinyloxirane (2) and isopropenyloxira ne (3), epoxide 2 is rapidly transformed into the corresponding vicinal rac emic diol 4, predominantly through a nonenzymatic hydrolysis reaction. At v ariance, epoxide 3 is mainly biotransformed into the diol 5 by microsomal e poxide hydrolase (mEH) to give, before 50% conversion, selectively (R)-3-me thyl-3-butene-1,2-diol, 5. The hydrolysis competes with the oxidation of th e monoepoxide 3 to the corresponding diepoxides 6. Epoxidation of 3 catalyz ed by P450 is characterized by a moderate stereoselectivity which, however, was strongly dependent on P450 induction. Treatment of rats with phenobarb ital (PB) (an inducer of P450 2B1 and 3A) leads to threo-(2R,2'R)-6 with a high selectivity, while with pyrazole (Pyr) (an inducer of P450 2E1), the f ormation of both erythro-(2S,2'R)- and threo-(2R,2'R)-6 is favored. The mEH -catalyzed hydrolysis of diepoxides 6 proceeds, although with a moderate tu rnover rate, with substrate and product diastereo- and enantioselection by nucleophilic attack on the more substituted oxirane ring to give selectivel y (2R,3S)-3,4-epoxy-2-methyl-1,2-diol (7). Both diols 4 and 5 may be furthe r oxidized on their double bond by P450. These reactions, which occur at a slow rate and are dependent on P450 induction with PB and Pyr, may be negli gible in the overall isoprene biotransformation. On the other hand, the epo xydiol 7, which is formed by hydrolysis of diepoxides 6 but it is itself no t hydrolyzable, may play an important role in the isoprene toxicity.