Medinsky M A, Schlosser P M, Bond J A
Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina 27709.
Environ Health Perspect. 1994 Nov;102 Suppl 9(Suppl 9):119-24. doi: 10.1289/ehp.94102s9119.
Benzene, an important industrial solvent, is also present in unleaded gasoline and cigarette smoke. The hematotoxic effects of benzene are well documented and include aplastic anemia and pancytopenia. Some individuals exposed repeatedly to cytotoxic concentrations of benzene develop acute myeloblastic anemia. It has been hypothesized that metabolism of benzene is required for its toxicity, although administration of no single benzene metabolite duplicates the toxicity of benzene. Several investigators have demonstrated that a combination of metabolites (hydroquinone and phenol, for example) is necessary to duplicate the hematotoxic effect of benzene. Enzymes implicated in the metabolic activation of benzene and its metabolites include the cytochrome P450 monooxygenases and myeloperoxidase. Since 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. Other organic molecules that are substrates for cytochrome P450 can inhibit the metabolism of benzene. For example, toluene has been shown to inhibit the oxidation of benzene in a noncompetitive manner. Enzyme inducers, such as ethanol, can alter the target tissue dosimetry of benzene metabolites by inducing enzymes responsible for oxidation reactions involved in benzene metabolism. 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, like conjugation and excretion.(ABSTRACT TRUNCATED AT 250 WORDS)
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。苯的血液毒性作用已有充分记录，包括再生障碍性贫血和全血细胞减少症。一些反复接触细胞毒性浓度苯的个体可发生急性髓细胞性贫血。据推测，苯的代谢是其产生毒性所必需的，尽管单一的苯代谢产物都不能复制苯的毒性。几位研究人员已证明，代谢产物的组合（例如对苯二酚和苯酚）对于复制苯的血液毒性作用是必要的。与苯及其代谢产物的代谢活化有关的酶包括细胞色素P450单加氧酶和髓过氧化物酶。由于苯及其羟基化代谢产物（苯酚、对苯二酚和儿茶酚）是相同细胞色素P450酶的底物，因此代谢产物之间可能存在竞争性相互作用。关于暴露于不同苯浓度的小鼠代谢产物形成的体内数据与苯对苯酚氧化的竞争性抑制一致。作为细胞色素P450底物的其他有机分子可抑制苯的代谢。例如，甲苯已被证明以非竞争性方式抑制苯的氧化。酶诱导剂，如乙醇，可通过诱导参与苯代谢的氧化反应的酶来改变苯代谢产物在靶组织中的剂量。苯及其代谢产物在靶组织骨髓中的剂量取决于活化过程（如酶促氧化）和失活过程（如结合和排泄）之间的平衡。（摘要截取自250字）
