INFLUENCE OF GENDER AND ACETONE PRETREATMENT ON BENZENE METABOLISM INMICE EXPOSED BY NOSE-ONLY INHALATION

Benzene (BZ) requires oxidative metabolism catalyzed by cytochrome P-4 50 2E1 (CYP 2E1) to exert its hematotoxic and genotoxic effects. We pr eviously reported that male mice have a two-fold higher maximum rate o f BZ oxidation compared with female mice; this correlates with the gre ater sensitivity of males to the genotoxic effects of BZ as measured b y micronuclei induction and sister chromatid exchanges. The aim of thi s study was to quantitate levels of BZ metabolites in urine and tissue s, and to determine whether the higher maximum rate of BZ oxidation in male mice would be reflected in higher levels of hydroxylated BZ meta bolites in tissues and water-soluble metabolites in urine. Male and fe male B6C3F, mice were exposed to 100 or 600 ppm C-14-BZ by nose-only i nhalation for 6 h. An additional group of male mice was pretreated wit h 1% acetone in drinking water for 8 d prior to exposure to 600 ppm BZ ; this group was used to evaluate the effect of induction of CYP 2E1 o n urine and tissue levels of BZ and its hydroxylated metabolites. BZ, phenol (PHE), and hydroquinone (HQ) were quantified in blood, liver, a nd bone marrow during exposure and postexposure, and water-soluble met abolites were analyzed in urine in the 48 h after exposure. Male mice exhibited a higher flux of BZ metabolism through the HQ pathway compar ed with females after exposure to either 100 ppm BZ (32.0 +/- 2.03 vs. 19.8 +/- 2.7%) or 600 ppm BZ (14.7 +/- 1.42 vs. 7.94 +/- 0.76%). Acet one pretreatment to induce CYP 2E1 resulted in a significant increase in both the percent and mass of urinary HQ glucuronide and muconic aci d in male mice exposed to 600 ppm BZ. This increase was paralleled by three- to fourfold higher steady-state concentrations of PHE and HQ in blood and bone marrow of acetone-pretreated mice compared with untrea ted mice. These results indicate that the higher maximum rate of BZ me tabolism in male mice is paralleled by a greater proportion of the tot al flux of BZ through the pathway for HQ formation, suggesting that th e metabolites formed along this pathway may be responsible for the gen otoxicity observed following BZ exposure.