METABOLISM OF 3-BUTENE-1,2-DIOL IN B6C3F1 MICE - EVIDENCE FOR INVOLVEMENT OF ALCOHOL-DEHYDROGENASE AND CYTOCHROME-P450

3-Butene-1,2-diol (BDD), a metabolite of 1,3-butadiene, is rapidly met abolized by B6C3F1 mice at doses ranging from 10 to 250 mg/kg. Calcula tion of plasma clearance suggested that the kinetics of BDD metabolism were dose-dependent. Clearance varied B-fold in this dose range. Urin ary excretion of BDD was also dose-dependent but did not exceed 5% of the administered dose. A small fraction of the dose (<1%) was excreted as glucuronide or sulfate conjugates. Benzylimidazole, a cytochrome P 450 inhibitor, decreased the clearance of BDD (25 mg/kg) by 44%, where as 4-methylpyrazole, an alcohol dehydrogenase and cytochrome P450 inhi bitor, decreased BDD clearance by 82%. BDD administration (250 mg/kg) resulted in depletion of hepatic and renal nonprotein thiols, by 48 an d 22%, respectively. Pretreatment of mice with 4-methylpyrazole provid ed partial protection against depletion of nonprotein thiols, whereas pretreatment with benzylimidazole was ineffective. Incubation of BDD w ith NADPH and mouse liver microsomes resulted in time-dependent inacti vation of p-nitrophenol hydroxylase (PNPH) activity, a marker for cyto chrome P450. Inclusion of glutathione, with or without glutathione per oxidase, did not attenuate the inactivation of PNPH, whereas deferoxam ine, superoxide dismutase, catalase, and mannitol provided modest prot ection. These results are consistent with suicide inhibition of PNPH b y BDD, with a minor role for reactive oxygen species in the loss of PN PH. Treatment of mice with BDD (250 mg/kg) inactivated hepatic microso mal PNPH activity by 50% after 60 min. These results suggest that BDD is extensively and rapidly metabolized in mice, and they provide evide nce for the formation of reactive intermediates that could play a role in the toxicity of 1,3-butadiene.