DIFFERENCES IN RATES OF BENZENE METABOLISM CORRELATE WITH OBSERVED GENOTOXICITY

Benzene (BZ) requires oxidative metabolism via cytochrome P450 2E1 (CY P 2E1) to exert its hematotoxic and genotoxic effects. Male mice are t wo- to threefold more sensitive to the genotoxic effects of BZ as meas ured by micronuclei induction and sister chromatid exchanges. The purp ose of our study was to investigate sex-related differences in the met abolism of BZ, phenol (PHE) and hydroquinone (HQ) in order to understa nd the metabolic basis for sex-dependent differences in BZ genotoxic s usceptibility in mice. Rates of BZ oxidation were quantitated using cl osed chamber gas uptake studies with male and female B6C3F1 mice expos ed to initial low (400-500 ppm), intermediate (1200-1300 ppm), and hig h (2600-2800 ppm) BZ concentrations. Acetone-pretreated and diethyldit hiocarbamate-pretreated male mice were also studied to determine the e xtent to which induction and inhibition of CYP 2E1, respectively, woul d alter in vivo BZ oxidation rates. Elimination of PHE and HQ from blo od was also compared in male and female mice to complement previously reported data on sex-related differences in urinary excretion of conju gated metabolites following iv administration of PHE. Based on PBPK mo del analysis, the optimized rate of metabolism (V-max) of BZ was almos t twofold higher in male mice (14.0 mu mol/hr-kg) than in female mice (7.9 mu mol/hr-kg); both male and female mice gas-uptake data were wel l fit with a K-M of 3.0 mu M. Pretreatment of male mice with 1% aceton e in drinking water for 8 days to specifically induce CYP 2E1. enhance d the rate of BZ oxidation by approximately fivefold (V-max = 75 mu mo l/hr-kg), while diethyldithiocarbamate pretreatment (320 mg/kg ip 30 m in prior to uptake study) completely inhibited BZ oxidation (V-max = 0 mu mol/hr-kg). Thus, both pretreatment regimens are potentially usefu l investigative tools to study the metabolic basis for benzene toxicit y. Elimination of PHE from blood was significantly faster in male mice , while elimination of HQ did not differ between male and female mice. Previous data indicated male mice produce more of the oxidized and co njugated metabolite, HQ glucuronide, after PHE administration, suggest ing that HQ production from PHE is greater in male mice. Taken togethe r, these data support the hypothesis that the greater sensitivity of m ale mice to the genotoxic effects of BZ compared to females is a funct ion of greater oxidative metabolism toward both BZ and PHE in male mic e. These data also suggest that differences in hepatic human CYP 2E1 a ctivity may be an important factor to consider when evaluating human r isk for benzene-induced hematotoxic and genotoxic effects. (C) 1996 Ac ademic Press, Inc.