title: Influence of gender and acetone pretreatment on benzene metabolism in mice exposed by nose-only inhalation.
abstract: Benzene (BZ) requires oxidative metabolism catalyzed by cytochrome P-450 2E1 (CYP 2E1) to exert its hematotoxic and genotoxic effects. We previously reported that male mice have a two-fold higher maximum rate of BZ oxidation compared with female mice; this correlates with the greater sensitivity of males to the genotoxic effects of BZ as measured by micronuclei induction and sister chromatid exchanges. The aim of this study was to quantitate levels of BZ metabolites in urine and tissues, and to determine whether the higher maximum rate of BZ oxidation in male mice would be reflected in higher levels of hydroxylated BZ metabolites in tissues and water-soluble metabolites in urine. Male and female B6C3F, mice were exposed to 100 or 600 ppm 14C-BZ by nose-only inhalation for 6 h. An additional group of male mice was pretreated with 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 on urine and tissue levels of BZ and its hydroxylated metabolites. BZ, phenol (PHE), and hydroquinone (HQ) were quantified in blood, liver, and bone marrow during exposure and postexposure, and water-soluble metabolites were analyzed in urine in the 48 h after exposure. Male mice exhibited a higher flux of BZ metabolism through the HQ pathway compared 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%). Acetone pretreatment to induce CYP 2E1 resulted in a significant increase in both the percent and mass of urinary HQ glucuronide and muconic acid 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 untreated mice. These results indicate that the higher maximum rate of BZ metabolism in male mice is paralleled by a greater proportion of the total flux of BZ through the pathway for HQ formation, suggesting that the metabolites formed along this pathway may be responsible for the genotoxicity observed following BZ exposure.
authors.affiliation: Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina, USA. kenyon.elaina@epamail.epa.gov
authors.forename: E M
authors.initials: EM
authors.lastname: Kenyon
authors.forename: M J
authors.initials: MJ
authors.lastname: Seaton
authors.forename: M W
authors.initials: MW
authors.lastname: Himmelstein
authors.forename: B
authors.initials: B
authors.lastname: Asgharian
authors.forename: M A
authors.initials: MA
authors.lastname: Medinsky
mesh_terms: D000096:Acetone / Q000494:pharmacology*; D000280:Administration, Inhalation; D000818:Animals; D001554:Benzene / Q000008:administration & dosage / Q000032:analysis / Q000378:metabolism*; D001853:Bone Marrow / Q000378:metabolism; D002250:Carbon Radioisotopes; D019392:Cytochrome P-450 CYP2E1 / Q000096:biosynthesis; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D006873:Hydroquinones / Q000097:blood / Q000652:urine; D006900:Hydroxylation / Q000187:drug effects; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D009296:Nasal Cavity; D019800:Phenol / Q000097:blood / Q000652:urine; D012737:Sex Factors; D012997:Solvents / Q000378:metabolism* / Q000494:pharmacology*
chemical_list: D002250:Carbon Radioisotopes; D006873:Hydroquinones; D012997:Solvents; D000096:Acetone; D019800:Phenol; D019392:Cytochrome P-450 CYP2E1; D001554:Benzene; C031927:hydroquinone