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Stereochemical and kinetic comparisons of mono- and diepoxide formation in the in vitro metabolism of isoprene by liver microsomes from rats, mice, and humans

Lookup NU author(s): Emeritus Professor Bernard Golding, Professor William Watson


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Isoprene (2-methylbuta-1,3-diene) is a large scale petrochemical used principally in the manufacture of synthetic rubbers. It is also produced by plants and trees and is formed endogenously in mammals as a major endogenous hydrocarbon. Mammalian metabolism of isoprene involves cytochrome P450-dependent monooxygenases to give the regioisomeric monoepoxides, prop-2-enyloxirane and 2-ethenyl-2-methyloxirane. The isoprene monoepoxides are further oxidized to the mutagenic diepoxides, 2-methyl-2,2′-bioxiranes. The present studies have investigated the stereochemistry and comparative rates of the metabolic epoxidation in vitro of isoprene to mono- and diepoxides by liver microsomes from rat, mouse, and human in order to identify stereochemical and kinetic differences between species in the formation of these epoxide metabolites, which are key to understanding the toxicology of isoprene. The assignments of stereochemistry were based on comparisons with synthetic standards, the syntheses for which are described. Comparative enzyme kinetic parameters (apparent Km and apparent Vmax values) for the in vitro formation of all of the monoepoxide and diepoxide stereoisomers have been obtained. The rates of formation of both mono- and diepoxides were greater in the rodent systems as compared with the human in vitro system. The results provide comparative kinetic data that have potential for modeling and assessing the relevance of the animal carcinogenicity data for man. The possibility of human interindividual variation was also investigated with liver preparations from several individual humans, but significant differences between individuals were not observed in the formation of the monoepoxides from isoprene.

Publication metadata

Author(s): Golding BT, Cottrell L, Mackay D, Zhang D, Watson WP

Publication type: Article

Publication status: Published

Journal: Chemical Research in Toxicology

Year: 2003

Volume: 16

Issue: 7

Pages: 933-944

ISSN (print): 0893-228X

ISSN (electronic): 1520-5010

Publisher: American Chemical Society


DOI: 10.1021/tx034061x

PubMed id: 12870896


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