Comparative metabolism of benzene and trans,trans-muconaldehyde to trans,trans-muconic acid in DBA/2N and C57BL/6 MICE

Abstract

Our laboratory recently identified trans, trans-muconaldehyde (MUC), a six-carbon diene dialdehyde, as a hematotoxic microsomal metabolite of benzene (Latriano et al, Proc Natl Acad Sci USA 83: 8356–8360, 1986). We also showed that MUC is metabolized in vitro to trans,trans-muconic acid (MA), a six-carbon diene dicarboxylic acid and known urinary metabolite of benzene. To elucidate further the role of ring-opened metabolites in benzene toxicity, the metabolism of benzene and MUC was examined in the benzene sensitive DBA/2N mouse strain and the less benzene sensitive C57BL/6 strain. A sensitive assay for urinary MA analysis was developed. The percent of benzene dose excreted as urinary MA within the first 24 hr after treatment decreased with an increase in benzene dose, i.e. from 9.8 to 0.4% in DBA/2N mice and from 17.6 to 0.2% in C57BL/6 mice treated with 0.5 to 880 mg/kg benzene. DBA/2N mice excreted significantly (P ⩽ 0.05) more MA compared with C57 BL/6 mice after treatment with hematotoxic benzene doses (220–880 mg/kg). At low benzene doses (0.5 to 2.5 mg/kg), C57BL/6 mice excreted significantly (P ⩽ 0.05) more MA compared with DBA/2N mice. There were no significant differences in the metabolism of MUC to MA between the two strains after treatment with 0.5 to 3.0 mg/kg. Furthermore, mice from both strains excreted similar amounts of muconic acid when treated with 0.7 to 7.1 mg/kg MA. These results are consistent with the hypothesis that reactive ring-opened metabolites such as trans, trans-muconaldehyde play a role in benzene hematotoxicity. Sensitivity towards benzene may be due, in part, to increased metabolism to ring-opened compounds.