Cellular and molecular basis for species, sex and tissue differences in 1,3-butadiene metabolism

Abstract

Species differences in 1,3-butadiene (BD) bioactivation and detoxication have been implicated in the greater sensitivity of mice to the carcinogenic effects of BD compared to rats, but the molecular basis for species differences in BD metabolism is not well understood. Previous and recent work conducted in this laboratory has examined the relative rates of BD oxidation to epoxybutene (EB) in male and female B6C3F1 mouse tissues, characterized the major cytochrome P450 enzymes involved in BD bioactivation in these tissues, and determined the potential utility of the freshly isolated hepatocyte model to investigate species differences in metabolism of BD and related compounds. Collectively, the results suggest a role for P450s 2E1, 2A5, and 4B1 in sex and tissue differences in BD bioactivation in the mouse. When coordinated metabolism of EB was investigated in male B6C3F1 mouse and Sprague–Dawley rat hepatocytes, the hepatocytes from both species were found to catalyze EB oxidation to meso- and (±)-diepoxybutane (DEB), EB hydrolysis to 3-butene-1,2-diol (BDD), and EB conjugation to form GSH conjugates (GSEB). The metabolite area under the curve (AUC) exhibited dependence on the EB concentration used. However, the EB activation/detoxication ratios with the mouse hepatocytes were much higher than the ratios obtained with the rat hepatocytes. These results illustrate the potential utility of the hepatocyte model for estimating flux through competing metabolic pathways and predicting in-vivo metabolism of EB. Collectively, the results may allow a better understanding of the molecular and kinetic basis of species differences in BD metabolism and may lead to a more accurate assessment of human risk.