Formation of hemoglobin and albumin adducts of benzene oxide in mouse, rat, and human blood
Formation of hemoglobin and albumin adducts of benzene oxide in mouse, rat, and human blood
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DOI：
10.1021/tx9701788
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发表时间：
1998-04-01
影响因子：
4.1
通讯作者：
Rappaport, SM
中科院分区：
文献类型：
--
作者：
Lindstrom, AB;Yeowell-O'Connell, K;Rappaport, SM
苯氧化物（BO）是细胞色素P450氧化苯产生的初始代谢产物，其形成和处置情况知之甚少。在本研究中，在体外研究了B6 C3 F（1）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为6.6 min（小鼠）、7.9 min（大鼠）和7.2 min（人）。对于BO与Hb和Alb的半胱氨酰残基之间的反应，估计了以下二级速率常数[以L为单位（Hb-或Alb-h的g）（-1）]：小鼠Hb = 1.16 x 10（-4），大鼠Hb = 15.4 x 10（-4），人Hb = 0.177 x 10（-4），小鼠Alb = 2.68 x 10（-4），大鼠Alb = 4.96 x 10（-4），人Alb = 5.19 x 10（-4）。这些速率常数与BO-加合物测量一起用于评估在已发表的动物和人类研究中体内苯引起的BO的全身剂量。在接受400 mg苯/kg体重单次灌胃给药的大鼠中，根据Alb加合物预测的BO剂量为2.62 x 10（3）nM BO-h，与报告的血液中BO的AUC（0-无穷大）= 1.09 x 10（3）nM BO-h非常相似。有趣的是，在相同大鼠中进行的Hb加合物测定预测了更高的剂量14.7 x 10（3）nM BO-h，表明红细胞内可能原位生成加合物。根据Alb加合物预测的BO剂量在接触苯的工人[13.3 nM BO-h（mg苯/kg体重）（-1）]和单次灌胃苯后的大鼠[8.42 nM BO-h（mg苯/kg体重）（-1）]中相似。另外的实验表明，Hb和Alb的粗分离物具有比透析蛋白质显著更高水平的BO加合物，这表明低分子量物质的缀合物在这些分离物中是丰富的。
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 B6C3F(1) 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 AUC(0-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.