title: Stereochemical course of the biotransformation of isoprene monoepoxides and of the corresponding diols with liver microsomes from control and induced rats.
abstract: The stereochemical course of the biotransformation of isoprene by liver enzymes from control and induced rats has been determined. Between the two primarily formed metabolites, 2-methyl-2-vinyloxirane (2) and isopropenyloxirane (3), epoxide 2 is rapidly transformed into the corresponding vicinal racemic diol 4, predominantly through a nonenzymatic hydrolysis reaction. At variance, epoxide 3 is mainly biotransformed into the diol 5 by microsomal epoxide hydrolase (mEH) to give, before 50% conversion, selectively (R)-3-methyl-3-butene-1,2-diol, 5. The hydrolysis competes with the oxidation of the monoepoxide 3 to the corresponding diepoxides 6. Epoxidation of 3 catalyzed by P450 is characterized by a moderate stereoselectivity which, however, was strongly dependent on P450 induction. Treatment of rats with phenobarbital (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 formation 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 turnover rate, with substrate and product diastereo- and enantioselection by nucleophilic attack on the more substituted oxirane ring to give selectively (2R,3S)-3,4-epoxy-2-methyl-1,2-diol (7). Both diols 4 and 5 may be further 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 negligible in the overall isoprene biotransformation. On the other hand, the epoxydiol 7, which is formed by hydrolysis of diepoxides 6 but it is itself not hydrolyzable, may play an important role in the isoprene toxicity.
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: V
authors.initials: V
authors.lastname: Tinagli
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; D002070:Butadienes / Q000378:metabolism*; D002849:Chromatography, Gas; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004790:Enzyme Induction; D004852:Epoxy Compounds / Q000378:metabolism*; D045782:Hemiterpenes; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D010420:Pentanes; D010634:Phenobarbital / Q000494:pharmacology; D011721:Pyrenes / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism
chemical_list: C415023:2-methyl-2-vinyloxirane; D002070:Butadienes; D004852:Epoxy Compounds; D045782:Hemiterpenes; D010420:Pentanes; D011721:Pyrenes; C415022:isopropenyloxirane; C005059:isoprene; D003577:Cytochrome P-450 Enzyme System; C030984:pyrene; D010634:Phenobarbital