Lindstrom A B, Yeowell-O'Connell K, Waidyanatha S, McDonald T A, Golding B T, Rappaport S M
Department of Environmental Sciences and Engineering, School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7400, USA.
Chem Res Toxicol. 1998 Apr;11(4):302-10. doi: 10.1021/tx9701788.
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.
关于苯氧化物（BO）的形成和处置知之甚少，苯氧化物是细胞色素P450氧化苯产生的初始代谢产物。在本研究中，在体外研究了B6C3F1小鼠、F344大鼠和人类血液中BO与血红蛋白（Hb）和白蛋白（Alb）的反应。BO在血液中的估计半衰期分别为6.6分钟（小鼠）、7.9分钟（大鼠）和7.2分钟（人类）。估计了BO与Hb和Alb的半胱氨酰残基之间反应的二级速率常数[单位为L（g Hb或Alb-h）-1]：小鼠Hb = 1.16×10（-）4，大鼠Hb = 15.4×10（-）4，人类Hb = 0.177×10（-）4，小鼠Alb = 2.68×10（-）4，大鼠Alb = 4.96×10（-）4，人类Alb = 5.19×10（-）4。这些速率常数与BO加合物测量值一起用于评估已发表的动物和人体研究中体内苯产生的BO全身剂量。在接受单次灌胃剂量400 mg苯/kg体重的大鼠中，根据Alb加合物预测的BO剂量为2.62×10（3）nM BO-h，与报道的血液中BO的AUC0-∞ = 1.09×10（3）nM BO-h非常相似。有趣的是，对同一只大鼠的Hb加合物检测预测剂量要高得多，为14.7×10（3）nM BO-h，这表明红细胞内可能原位生成加合物。在接触苯的工人中[13.3 nM BO-h（mg苯/kg体重）-1]和单次灌胃苯后的大鼠中[8.42 nM BO-h（mg苯/kg体重）-1]，根据Alb加合物预测的BO剂量相似。额外的实验表明，Hb和Alb的粗提取物中的BO加合物水平明显高于透析后的蛋白质，这表明这些提取物中低分子量物质的缀合物含量丰富。
