Chemical research in toxicology

Oxidation of 3-butene-1,2-diol by alcohol dehydrogenase.

PMID 8902267


3-Butene-1,2-diol (BDD) is a metabolite of the carcinogenic petrochemical 1,3-butadiene. BDD is produced by cytochrome P450-mediated oxidation of 1,3-butadiene to butadiene monoxide, followed by enzymatic hydrolysis by epoxide hydrolase. The metabolic disposition of BDD is unknown. The current work characterizes BDD oxidation by purified horse liver alcohol dehydrogenase (ADH) and by cytosolic ADH from mouse, rat, and human liver. BDD is oxidized by purified horse liver ADH in a stereoselective manner, with (S)-BDD oxidized at approximately 7 times the rate of (R)-BDD. Attempts to detect and identify metabolites of BDD using purified horse liver ADH demonstrated formation of a single stable metabolite, 1-hydroxy-2-butanone (HBO). A second possible metabolite, 1-hydroxy-3-butene-2-one (HBONE), was tentatively identified by GC/MS, but HBONE formation could not be clearly attributed to BDD oxidation, possibly due to its rapid decomposition in the incubation mixture. Formation of HBO by ADH was dependent upon reaction time, protein concentration, substrate concentration, and the presence of NAD. Inclusion of GSH or 4-methylpyrazole in the incubation mixture resulted in inhibition of HBO formation. Based on these results and other lines of evidence, a mechanism is proposed for HBO formation involving generation of several potentially reactive intermediates which could contribute to toxicity of 1,3-butadiene in exposed individuals. Comparison of kinetics of BDD oxidation in rat, mouse, and human liver cytosol did not reveal significant differences in catalytic efficiency (Vmax/K(m)) between species. These results may contribute to a better understanding of 1,3-butadiene metabolism and toxicity.

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3,4-Dihydroxy-1-butene, ≥99%