Study on the cytochrome P-450-and glutathione-dependent biotransformation of trichloroethylene in humans
Study on the cytochrome P-450-and glutathione-dependent biotransformation of trichloroethylene in humans
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DOI：
10.1007/s004200000198
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发表时间：
2001-03-01
影响因子：
3
通讯作者：
Wilmer, JW
中科院分区：
文献类型：
--
作者：
Bloemen, LJ;Monster, AC;Wilmer, JW
研究志愿者在受控重复暴露和职业条件下三氯乙烯（TRI）的细胞色素P-450和谷胱甘肽依赖性生物转化对人体的贡献。方法：志愿者暴露于TRI，在50和100 ppm下重复暴露15分钟。该暴露时间表导致TRI的内部剂量分别为1.30和2.40 mmol。采集尿样至少45 h。还收集了职业接触工人的尿样。分析样品中已知的TRI人体代谢物、三氯乙醇（TCE）、三氯乙酸（TCA）和巯基尿酸N-乙酰基-S-（二氯乙烯基）-L-半胱氨酸（DCV-NAC）的两种区域异构形式，以及（二氯乙烯基）-L-半胱氨酸（DCVC）。为了进一步阐明TRI在人体中的代谢，我们分析了样品中的二氯乙酸以及脱氨基后1，2和2，2-二氯乙烯基-L-半胱氨酸的拟定分解产物：3-巯基乳酸、3-巯基丙酮酸和2-巯基乙酸的S-共轭物。结果：志愿者尿液中未检出谷胱甘肽代谢产物。在职业暴露于0.4和21 ppm [8小时时间加权平均（TWA）I]水平的TRI的工人中，在第4个工作日结束时和第二天早上收集的尿样中DCV-NAC水平低于检测限（0.04 μ mol/l）。这证实了Bernauer et al（1996）的发现，即这些代谢物在人体中以极低水平排泄。DCVC和二氯乙烯基-S-半胱氨酸结合物通过脱氨基作用的6种假定代谢物的尿液水平也低于0.04 μ mol/l，表明至多0.05%的剂量以这些代谢物的形式排泄。这些数据进一步加强了长期接触工人谷胱甘肽介导的代谢活性非常低的论点。结论：本研究提供了额外的数据，表明谷胱甘肽介导的代谢在暴露于TRI的人体中的重要性较小。尽管有相反的迹象，但不能完全排除半胱氨酸结合物通过D-裂解酶的显著代谢，这可能导致毒性代谢物。
To investigate in humans the contribution of the cytochrome P-450- and glutathione-dependent biotransformation of trichloroethylene (TRI) under controlled repeated exposure in volunteers, and under occupational conditions. Methods: Volunteers were exposed to TRI, using repeated 15 min exposures at 50 and 100 ppm. This exposure schedule resulted in internal doses of 1.30 and 2.40 mmol of TRI respectively. Urine samples were collected for a minimum of 45 h. Urine samples were also collected from occupationally exposed workers. The samples were analysed for the known human metabolites of TRI, trichloroethanol (TCE), trichloroacetic acid (TCA) and both regio-isomeric forms of the mercapturic acid N-acetyl-S-(dichlorovinyl)-L-cysteine (DCV-NAC), and for (dichlorovinyl)-L-cysteine (DCVC). In order to further elucidate the metabolism of TRI in humans, we analysed samples for dichloroacetic acid and for the proposed break-down products of 1,2 and 2,2-dichlorovinyl-L-cysteine after deamination: the S-conjugates of 3-mercaptolactic acid, 3-mercaptopyruvic acid and 2-mercaptoacetic acid. Results: None of the glutathione metabolites was found in urine of volunteers. In workers occupationally exposed to TRI at levels between 0.4 and 21 ppm [8-h time-weighted average (TWA)I, levels of DCV-NAC in urine samples collected at the end of the 4th working day and also next morning were below detection limit (0.04 mu mol/l). This confirms the findings of Bernauer et al, (1996) that these metabolites are excreted at very low levels in humans, Urinary levels of DCVC and six postulated metabolites of dichlorovinyl-S-cysteine conjugates via deamination were also below 0.04 mu mol/l, indicating that at most 0.05% of the dose is excreted in the form of these metabolites. These data further strengthen the argument for a very low activity of glutathione-mediated metabolism for chronically exposed workers. Conclusions: This study gives additional data which indicate that glutathione-mediated metabolism is of minor importance in humans exposed to TRI, In spite of indications to the contrary, significant metabolism of the cysteine conjugate via D-lyase, which could result in a toxic metabolite, cannot be ruled out completely.