期刊
TOXICOLOGY AND APPLIED PHARMACOLOGY
卷 169, 期 1, 页码 52-58出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1006/taap.2000.9038
关键词
styrene; styrene oxide; metabolism; stereoselectivity; enantiomers; epoxide hydrolase; interindividual variation
Styrene is an industrial solvent which is mainly oxidized by cytochrome P450 to an electrophilic, chiral epoxide metabolite: styrene-7,8-oxide (SO). SO has cytotoxic and genotoxic properties; the (R)-enantiomer is more mutagenic to Salmonella typhimurium TA 100 in the Ames test than the (S)-enantiomer. Detoxication proceeds via microsomal epoxide hydrolase (mEH). Interindividual differences in mEH activity as well as differences in mEH enantioselectivity are important factors for toxic effects of SO. To study the extent of the interindividual variation, microsomal preparations of 20 human livers were incubated with (R)- and (S)-SO separately (1-2000 muM) and Michaelis-Menten kinetics were determined. In addition, samples were genotyped for two genetic polymorphisms of the mEH gene. V-max, K-m and V-max/K-m values of both enantiomers differed three- to fivefold between the livers. No association of the enzyme constants with the genetic polymorphisms of the epoxide hydrolase gene was found. Hydrolysis of the styrene oxide enantiomers proceeded in an enantioselective manner, with the (S)-enantiomer having an approximately six times higher K-m and five times higher V-max than the (R)-enantiamer. In vivo, both SO enantiomers are formed; therefore, time course incubations with racemic SO were carried out in vitro to investigate possible interactions between the enantiomers. When racemic SO was used as a substrate, the (R)-enantiomer acted as an inhibitor on the hydrolysis of the (S)-enantiomer. These results indicate that mEH-mediated hydrolysis of SO is subject to appreciable interindividual variation and that hydrolysis of the more toxic enantiomer is favored. (C) 2000 Academic Press.
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