CRITICAL ISSUES IN BENZENE TOXICITY AND METABOLISM - THE EFFECT OF INTERACTIONS WITH OTHER ORGANIC-CHEMICALS ON RISK ASSESSMENT
CRITICAL ISSUES IN BENZENE TOXICITY AND METABOLISM - THE EFFECT OF INTERACTIONS WITH OTHER ORGANIC-CHEMICALS ON RISK ASSESSMENT
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DOI：
10.1289/ehp.94102s9119
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发表时间：
1994-11-01
影响因子：
10.4
通讯作者：
BOND, JA
中科院分区：
文献类型：
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作者：
MEDINSKY, MA;SCHLOSSER, PM;BOND, JA
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。苯的血液毒性作用是有据可查的，包括再生障碍性贫血和全血细胞减少。有些人反复暴露于细胞毒性浓度的苯发展急性成髓细胞性贫血。尽管施用任何单一的苯代谢物都不能复制苯的毒性，但已经假设苯的毒性需要苯的代谢。一些研究者已经证明，代谢物（例如对苯二酚和苯酚）的组合是复制苯的血液毒性作用所必需的。参与苯及其代谢物代谢活化的酶包括细胞色素P450单加氧酶和髓过氧化物酶。由于苯及其羟基化代谢物（苯酚、对苯二酚和邻苯二酚）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。暴露于不同苯浓度的小鼠的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。作为细胞色素P450底物的其他有机分子可以抑制苯的代谢。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，可以通过诱导负责苯代谢中涉及的氧化反应的酶来改变苯代谢物的靶组织剂量测定。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）的平衡。基于生物学的剂量测定模型，包括苯通量的重要决定因素，包括与其他化学品的相互作用，将能够预测目标组织剂量的苯和代谢物在低暴露浓度相关的人类。
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. 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.