Formation of Hemoglobin and Albumin Adducts of Benzene Oxide in Mouse, Rat, and Human Blood

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Abstract
Little is known about the formation and disposition of benzene oxide (BO), the initial metabolite arising from oxidation of benzene by cytochrome P450. In this study, reactions of BO with hemoglobin (Hb) and albumin (Alb) were investigated in blood from B6C3F1 mice, F344 rats, and humans in vitro. The estimated half-lives of BO in blood were 6.6 min (mice), 7.9 min (rats), and 7.2 min (humans). The following second-order rate constants were estimated for reactions between BO and cysteinyl residues of Hb and Alb [in units of L (g of Hb- or Alb-h)-1]: mouse Hb = 1.16 x 10(-)4, rat Hb = 15.4 x 10(-)4, human Hb = 0.177 x 10(-)4, mouse Alb = 2.68 x 10(-)4, rat Alb = 4.96 x 10(-)4, and human Alb = 5.19 x 10(-)4. These rate constants were used with BO-adduct measurements to assess the systemic doses of BO arising from benzene in vivo in published animal and human studies. Among rats receiving a single gavage dose of 400 mg of benzene/kg of body weight, the BO dose of 2.62 x 10(3) nM BO-h, predicted from Alb adducts, was quite similar to the reported AUC0-infinity = 1.09 x 10(3) nM BO-h of BO in blood. Interestingly, assays of Hb adducts in the same rats predicted a much higher dose of 14.7 x 10(3) nM BO-h, suggesting possible in situ generation of adducts within the erythrocyte. Doses of BO predicted from Alb adducts were similar in workers exposed to benzene [13.3 nM BO-h (mg of benzene/kg of body weight)-1] and in rats following a single gavage dose of benzene [8. 42 nM BO-h (mg of benzene/kg of body weight)-1]. Additional experiments indicated that crude isolates of Hb and Alb had significantly higher levels of BO adducts than dialyzed proteins, suggesting that conjugates of low-molecular-weight species were abundant in these isolates.