PRODUCTION OF BENZOQUINONE ADDUCTS WITH HEMOGLOBIN AND BONE-MARROW PROTEINS FOLLOWING ADMINISTRATION OF [13C6]BENZENE TO RATS

Adduction of hemoglobin (Hb) and bone-marrow proteins with 1,2- and 1,4-benzoquinone (1,2-BQ and 1,4-BQ) and 4,4'-diphenoquinone was examined following oral administration of [C-13(6)]benzene to F344 rats. Linear production of [C-13(6)]1,4-BQ adducts was observed with both Hb and bone-marrow proteins over the entire range of dosages of 0-400 mg/kg. The slopes of the regressions were 3.4 x 10(-4) (r2 = 0.997) and 1.6 x 10(-3) (r2 = 0.926) nmol/g protein/mg/kg respectively, for Hb and bone-marrow proteins. Production of [C-13(6)]1,2-BQ adducts of Hb and bone-marrow proteins also increased with benzene dosage. Although the shapes of the relationships between 1,2-BQ adducts and dosage were nonlinear, the levels were approximately 10 times greater than those associated with 1,4-BQ, suggesting a significantly greater benzene-specific dose of 1,2-BQ. Adducts of 4,4'-diphenoquinone were not detected. High background levels of [C-12(6)]adducts of 1,2-BQ and 1,4-BQ were found in Hb and bone-marrow proteins as might be expected from the many dietary sources of the phenolic precursors of the benzoquinones, i.e. phenol, catechol and hydroquinone. Background levels of the 1,2-BQ and 1,4-BQ adducts were 27.3 and 11.5 nmol/g in Hb and 44.6 and 25.6 nmol/g in the bone-marrow proteins respectively. Interestingly, the production of benzene-specific adducts represented only a small fraction (< 4%) of the background levels of the same adducts. If the genotoxicity of benzene is, indeed, related to the in vivo production of BQ isomers, our results suggest that very large exposures to benzene would be needed to produce detectable increases in adduct levels and the associated risks of leukemia.