Metabolism of butadiene monoxide by freshly isolated hepatocytes from mice and rats: different partitioning between oxidative, hydrolytic, and conjugation pathways. Drug Metab. Dispos

This paper is available online at http://dmd.aspetjournals.org ABSTRACT: 1,3-Butadiene (BD) is a multisite carcinogen in rodents, with mice being much more susceptible than rats. This species difference in carcinogenicity has been attributed to differences in metabolism. In this study, coordinated metabolism of butadiene monoxide (BMO, 5, 25, and 250 M), the primary reactive metabolite of BD, was investigated in freshly isolated male B6C3F1 mouse and Sprague-Dawley rat hepatocytes. The hepatocytes from both species catalyzed BMO oxidation to meso-and (؎)-diepoxybutane (DEB), BMO hydrolysis to 3-butene-1,2-diol (BDD), and BMO conjugation with glutathione (GSH) to form GSH conjugates (GSBMO). Metabolite area under the curve (AUC) exhibited dependence on the BMO concentration and incubation time (0-45 min). However, the observed BMO activation/detoxication ratios (obtained by dividing the AUC for total DEB by the summed AUC values for BDD and GSBMO) with mouse hepatocytes were approximately 15-to 40-fold higher than the corresponding ratios observed with rat hepatocytes. At 5 M BMO, bioactivation in the mouse exceeded detoxication by approximately 2-fold, whereas at the 250 M concentration, activation was only about 31% of total detoxication. In rat hepatocytes, the activation-detoxication ratio was relatively independent of the initial BMO concentration, with flux through the oxidative pathway at approximately 2 to 5% of the total detoxication. These results, which are more consistent with in vivo mouse and rat toxicity data than the metabolic rates obtained with subcellular fractions, illustrate the potential utility of the isolated hepatocyte model for estimating flux through competing metabolic pathways and predicting in vivo metabolism of BMO and its parent compound, BD