Seaton M J, Schlosser P, Medinsky M A
Chemical Industry Institute of Toxicology, Research Triangle Park, NC 27709, USA.
Carcinogenesis. 1995 Jul;16(7):1519-27. doi: 10.1093/carcin/16.7.1519.
In addition to industrial sources, benzene is present in the environment as a component of cigarette smoke and automobile emissions. Toxicity of benzene most likely results from oxidative metabolism of benzene to reactive products. However, susceptibility to these toxic effects may be related to a balance between activation (phase I) and detoxication (phase II) reactions. In the present study, we have estimated kinetic parameters of the two major detoxication reactions for benzene metabolites--phenol sulfation and hydroquinone glucuronidation--in liver subcellular fractions from 10 humans, and single samples from mice and rats. The extent of oxidative metabolism of benzene by these liver samples has been reported previously. Here, initial rates of phenol sulfation varied 3-fold (range 0.309-0.919 nmol/mg protein/min) among human samples. Measured rates were faster in rats (1.195 nmol/mg protein/min) than in mice (0.458 nmol/mg protein/min). Initial rates of hydroquinone glucuronidation by human samples also varied 3-fold (range 0.101-0.281 nmol/mg protein/min). Hydroquinone glucuronidation was more rapid by mouse microsomes (0.218 nmol/mg protein/min) than by rat microsomes (0.077 nmol/mg protein/min). To integrate interindividual differences in various enzyme activities, a physiological compartmental model was developed that incorporates rates of both conjugation reactions and oxidation reactions. Model equations were solved for steady-state concentrations of phenol and hydroquinone attained in human, mouse and rat blood during continuous exposure to benzene (0.01 microM in blood). Among the 10 human subjects, steady-state concentrations of phenol varied 6-fold (range 0.38-2.17 nM) and steady-state concentrations of hydroquinone varied 5-fold (range 6.66-31.44 nM). Predicted steady-state concentrations of phenol were higher in mice compared with rats (2.28 and 0.83 nM respectively). Likewise, higher steady-state concentrations of hydroquinone were predicted in mice than in rats (42.44 and 17.99 nM respectively). Predicted steady-state concentrations of phenol and hydroquinone in mice were higher than predictions for the 10 human subjects, whereas predicted concentrations for rats fell among the human values. As such, our results underscore the importance of considering the balance between activation and detoxication reactions in the elimination of toxicants. Model simulations suggest that both phase I and phase II pathways influence the relative risk from exposure to benzene.
除工业来源外，苯在环境中还作为香烟烟雾和汽车尾气的成分存在。苯的毒性很可能源于苯氧化代谢生成活性产物。然而，对这些毒性作用的易感性可能与活化（I相）和解毒（II相）反应之间的平衡有关。在本研究中，我们估算了10名人类肝脏亚细胞组分以及小鼠和大鼠的单个样本中苯代谢物的两种主要解毒反应——苯酚硫酸化和对苯二酚葡萄糖醛酸化——的动力学参数。这些肝脏样本对苯的氧化代谢程度此前已有报道。在此，人类样本中苯酚硫酸化的初始速率变化了3倍（范围为0.309 - 0.919 nmol/mg蛋白质/分钟）。测得的大鼠速率（1.195 nmol/mg蛋白质/分钟）比小鼠（0.458 nmol/mg蛋白质/分钟）快。人类样本对对苯二酚葡萄糖醛酸化的初始速率也变化了3倍（范围为0.101 - 0.281 nmol/mg蛋白质/分钟）。小鼠微粒体对对苯二酚的葡萄糖醛酸化（0.218 nmol/mg蛋白质/分钟）比大鼠微粒体（0.077 nmol/mg蛋白质/分钟）更快。为整合各种酶活性的个体差异，构建了一个生理房室模型，该模型纳入了结合反应和氧化反应的速率。求解模型方程得出在持续接触苯（血液中浓度为0.01 μM）期间人类、小鼠和大鼠血液中苯酚和对苯二酚的稳态浓度。在10名人类受试者中，苯酚的稳态浓度变化了6倍（范围为0.38 - 2.17 nM），对苯二酚的稳态浓度变化了5倍（范围为6.66 - 31.44 nM）。预测小鼠中苯酚的稳态浓度高于大鼠（分别为2.28和0.83 nM）。同样，预测小鼠中对苯二酚的稳态浓度高于大鼠（分别为42.44和17.99 nM）。预测小鼠中苯酚和对苯二酚的稳态浓度高于对10名人类受试者的预测值，而大鼠的预测浓度则处于人类数值范围内。因此，我们的结果强调了在消除毒物过程中考虑活化和解毒反应平衡的重要性。模型模拟表明I相和II相途径均影响接触苯的相对风险。
