Inhibition of cytochrome P450 2E1 decreases, but does not eliminate, genotoxicity mediated by 1,3-butadiene

1,3-Butadiene (BD), a rodent carcinogen, is metabolized to mutagenic and DN A-reactive epoxides. In vitro data suggest that this oxidation is mediated by cytochrome P450 2E1 (CYP2E1). In this study, we tested the hypothesis th at oxidation of ED by CYP2E1 is required for genotoxicity to occur. Inhalat ion exposures were conducted with B6C3F1 mice using a closed-chamber techni que, and the maximum rate of butadiene oxidation was estimated. The total a mount of butadiene metabolized was then correlated with the frequency of mi cronuclei (MN), Three treatment groups were used: (1) mice with no pretreat ment; (2) mice pretreated with 1,2-trans-dichloroethylene (DCE), a specific CYP2E1 inhibitor; and (3) mice pretreated with 1-aminobenzotriazole (ABT), an irreversible inhibitor of cytochromes P450, Mice in all 3 groups were e xposed to an initial ED concentration of 1100 ppm, and the decline in conce ntration of ED in the inhalation chamber with time, due to uptake and metab olism of ED, was monitored using gas chromatography, A physiologically base d pharmacokinetic model was used to analyze the gas uptake data, estimate V -max for ED oxidation, and compute the total amount of ED metabolized, Mode l simulations of the gas uptake data predicted the maximum rate of ED oxida tion would be reduced by 60% and 100% for the DCE- and ABT-pretreated group s, respectively. Bone marrow was harvested 24 h after the onset of the inha lation exposure and analyzed for frequency of micronuclei in polychromatic erythrocytes (MN-PCE). The frequency of MN-PCE per 1000 PCE in mice exposed to ED was 28.2 +/- 3.1, 19.8 +/- 2.5, and 12.3 +/- 1.9, for the mice with no pretreatment, DCE-pretreated mice and ABT-pretreated mice, respectively. Although inhibition of CYP2E1 decreased ED-mediated genotoxicity, it did n ot completely eliminate genotoxic effects, These data suggest that other P4 50 isoforms may contribute significantly to the metabolic activation of ED and resultant genotoxicity.