Interspecies differences in metabolism and kinetics of 1,3-butadiene, isobutene and styrene

Investigations on the pharmacokinetics of inhalation of 1,3-butadiene and its primary reactive intermediate, epoxybutene, in mice and rats have demonstrated reasonably clearly that the species differences observed in the carcinogenicity of butadiene are accompanied by species differences in its metabolism. Mice metabolize butadiene to epoxybutene faster than rats but have a limited capacity for detoxification and accumulation of the reactive epoxide intermediate; these characteristics are viewed as major determinants of the greater susceptibility of mice to butadiene. The detection of alkylation products of epoxybutene and diepoxybutane with guanine residues in DNA of livers of mice exposed to butadiene indicate that eposybutene is further biotransformed to diepoxybutane in this species. This assumption is supported by the finding that butadiene induces cross-linking between DNA and proteins in mice, which can be attributed to the bifunctional alkylating diepoxybutane. Quantitative differences between rats and mice in butadiene metabolism and in the biological effectiveness of the reactive epoxide intermediates reflect the activities of different enzymes in butadiene metabolism. Epoxybutene is metabolized primarily via glutathione S-transferase-mediated pathways, resulting in glutathione depletion, increased toxicity at higher doses and covalent binding of reactive butadiene intermediates. A drastic depletion of non-protein sulfhydryl is observed in the tissues of mice but not of rats after acute exposure to butadiene. Isobutene (2-methylpropene) is converted by hepatic monooxygenase(s) to the epoxide, 2,2-dimethyloxirane. This epoxide, when appropriately tested, was mutagenic to Salmonellatyphimurium strains TA100 and TA1535. Addition of an exogenous metabolic system diminished the mutagenicity of 2,2-dimethyloxirane.(ABSTRACT TRUNCATED AT 250 WORDS)