Trichloroethylene biotransformation and its role in mutagenicity, carcinogenicity and target organ toxicity.
Trichloroethylene biotransformation and its role in mutagenicity, carcinogenicity and target organ toxicity.
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DOI：
10.1016/j.mrrev.2014.04.003
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发表时间：
2014-10
影响因子：
5.3
通讯作者：
Rusyn, Ivan
中科院分区：
文献类型：
--
作者：
Lash, Lawrence H.;Chiu, Weihsueh A.;Guyton, Kathryn Z.;Rusyn, Ivan
关键词：
代谢对于三氯乙烯（TCE）的致突变性、致癌性和其他不良健康影响至关重要。尽管三氯乙烯的体积相对较小，化学结构简单，但其代谢相当复杂，产生多种中间体和终产物。实验动物和人体数据表明，TCE代谢通过两个主要途径发生：细胞色素P450（CYP）依赖性氧化和谷胱甘肽（GSH）结合催化的谷胱甘肽S-转移酶（GST）。在此，我们回顾最近的数据表征TCE加工和通量通过这些途径。我们描述了催化酶，它们的调节和组织定位，以及运输和代谢产物的器官间加工的证据。我们解决了TCE代谢产物的化学反应性，突出这些最终产品的致突变性的数据。在暴露的人类和其他物种（主要是大鼠和小鼠）尿液中鉴定出关键代谢物，特别是三氯乙酸盐（TCA）、二氯乙酸盐（DCA）、三氯乙醇及其葡糖苷酸（TCOH和TCOG）和N-乙酰基-S-（1，2-二氯乙烯基）-L-半胱氨酸（NAcDCVC），证明了这两种代谢途径在体内的功能。该途径主要产生化学稳定的终产物。然而，GST途径结合物S-（1，2-二氯乙烯基）谷胱甘肽（DCVG）被进一步加工成多种已知具有致突变性的高反应性物质，尤其是在原位代谢发生的肾脏中。TCE代谢在性别、物种、组织和个体之间差异很大。代谢三氯乙烯及其中间产物的几种关键酶的遗传多态性导致代谢谱和速率的变异。总而言之，表征TCE复杂代谢的证据可以为预测不良反应提供信息，包括诱变，致癌作用以及急性和慢性器官特异性毒性。
Metabolism is critical for the mutagenicity, carcinogenicity, and other adverse health effects of trichloroethylene (TCE). Despite the relatively small size and simple chemical structure of TCE, its metabolism is quite complex, yielding multiple intermediates and end-products. Experimental animal and human data indicate that TCE metabolism occurs through two major pathways: cytochrome P450 (CYP)-dependent oxidation and glutathione (GSH) conjugation catalyzed by GSH S-transferases (GSTs). Herein we review recent data characterizing TCE processing and flux through these pathways. We describe the catalytic enzymes, their regulation and tissue localization, as well as the evidence for transport and inter-organ processing of metabolites. We address the chemical reactivity of TCE metabolites, highlighting data on mutagenicity of these end-products. Identification in urine of key metabolites, particularly trichloroacetate (TCA), dichloroacetate (DCA), trichloroethanol and its glucuronide (TCOH and TCOG), and N-acetyl-S-(1,2-dichlorovinyl)-L-cysteine (NAcDCVC), in exposed humans and other species (mostly rats and mice) demonstrates function of the two metabolic pathways in vivo. The CYP pathway primarily yields chemically stable end-products. However, the GST pathway conjugate S-(1,2-dichlorovinyl)glutathione (DCVG) is further processed to multiple highly reactive species that are known to be mutagenic, especially in kidney where in situ metabolism occurs. TCE metabolism is highly variable across sexes, species, tissues and individuals. Genetic polymorphisms in several of the key enzymes metabolizing TCE and its intermediates contribute to variability in metabolic profiles and rates. In all, the evidence characterizing the complex metabolism of TCE can inform predictions of adverse responses including mutagenesis, carcinogenesis, and acute and chronic organ-specific toxicity.
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DOI：
10.1186/1745-6673-2-13
发表时间：
2007-11-12
期刊：
Journal of occupational medicine and toxicology (London, England)
影响因子：
--
作者：
Charbotel, Barbara;Gad, Sophie;Richard, Stephane
通讯作者：
Richard, Stephane
影响因子：
10.4
作者：
Bronley-DeLancey A;McMillan DC;McMillan JM;Jollow DJ;Mohr LC;Hoel DG
通讯作者：
Hoel DG
影响因子：
6.1
作者：
Bruning, T;Weirich, G;Brauch, H
通讯作者：
Brauch, H
DOI：
10.1007/s004200000198
发表时间：
2001-03-01
影响因子：
3
作者：
Bloemen, LJ;Monster, AC;Wilmer, JW
通讯作者：
Wilmer, JW
影响因子：
3.5
作者：
Brauch, H;Weirich, G;Brüning, T
通讯作者：
Brüning, T