Medinsky M A, Kenyon E M, Seaton M J, Schlosser P M
Chemical Industry Institute of Toxicology, Research Triangle Park, NC 27709-1237, USA.
Environ Health Perspect. 1996 Dec;104 Suppl 6(Suppl 6):1399-404. doi: 10.1289/ehp.961041399.
Benzene, an important industrial solvent, is also present in unleaded gasoline and cigarette smoke. The hematotoxic effects of benzene in humans are well documented and include aplastic anemia, pancytopenia, and acute myelogenous leukemia. However, the risks of leukemia at low exposure concentrations have not been established. A combination of metabolites (hydroquinone and phenol, for example) may be necessary to duplicate the hematotoxic effect of benzene, perhaps due in part to the synergistic effect of phenol on myeloperoxidase-mediated oxidation of hydroquinone to the reactive metabolite benzoquinone. Because benzene and its hydroxylated metabolites (phenol, hydroquinone, and catechol) are substrates for the same cytochrome P450 enzymes, competitive interactions among the metabolites are possible. In vivo data on metabolite formation by mice exposed to various benzene concentrations are consistent with competitive inhibition of phenol oxidation by benzene. In vitro studies of the metabolic oxidation of benzene, phenol, and hydroquinone are consistent with the mechanism of competitive interaction among the metabolites. The dosimetry of benzene and its metabolites in the target tissue, bone marrow, depends on the balance of activation processes such as enzymatic oxidation and deactivation processes such as conjugation and excretion. Phenol, the primary benzene metabolite, can undergo both oxidation and conjugation. Thus the potential exists for competition among various enzymes for phenol. Zonal localization of phase I and phase II enzymes in various regions of the liver acinus also impacts this competition. Biologically based dosimetry models that incorporate the important determinants of benzene flux, including interactions with other chemicals, will enable prediction of target tissue doses of benzene and metabolites at low exposure concentrations relevant for humans.
苯是一种重要的工业溶剂，也存在于无铅汽油和香烟烟雾中。苯对人体的血液毒性作用已有充分记录，包括再生障碍性贫血、全血细胞减少症和急性髓性白血病。然而，低暴露浓度下白血病的风险尚未确定。可能需要多种代谢物（例如对苯二酚和苯酚）的组合才能复制苯的血液毒性作用，这可能部分归因于苯酚对髓过氧化物酶介导的对苯二酚氧化为活性代谢物苯醌的协同作用。由于苯及其羟基化代谢物（苯酚、对苯二酚和儿茶酚）是相同细胞色素P450酶的底物，因此代谢物之间可能存在竞争性相互作用。小鼠暴露于不同苯浓度下代谢物形成的体内数据与苯对苯酚氧化的竞争性抑制一致。苯、苯酚和对苯二酚代谢氧化的体外研究与代谢物之间竞争性相互作用的机制一致。苯及其代谢物在靶组织骨髓中的剂量测定取决于激活过程（如酶促氧化）和失活过程（如结合和排泄）之间的平衡。苯酚是苯的主要代谢物，可进行氧化和结合。因此，各种酶之间可能存在对苯酚的竞争。肝腺泡不同区域I相和II相酶的区域定位也会影响这种竞争。纳入苯通量重要决定因素（包括与其他化学物质的相互作用）的基于生物学的剂量测定模型将能够预测与人类相关的低暴露浓度下苯和代谢物在靶组织中的剂量。
