Bolt H M, Filser J G, Laib R J, Ottenwälder H
Arch Toxicol Suppl. 1980;3:129-42. doi: 10.1007/978-3-642-67389-4_10.
Vinyl chloride and vinyl bromide are metabolically activated by liver microsomal enzymes to intermediates that covalently bind to proteins and nucleic acids. Several lines of evidence suggest the involvement of the epoxides, i.e., chloroethylene oxide or bromoethylene oxide. Proven targets for alkylation are adenine, cytosine and guanine moieties in nucleic acids, and sulfhydryl groups of proteins. For all the halogenated ethylenes studied so far, including vinyl chloride and vinyl bromide, metabolism in vivo is a dose-dependent, saturable process. The metabolic capacity of rats is saturated at atmospheric concentrations of 250 ppm vinyl chloride and 55 ppm vinyl bromide. As recent reports describe a diminishment of hepatocellular glutathione in rats after exposure to vinyl chloride concentrations of 50 ppm and more, we carried out a series of experiments measuring covalent binding of vinyl chloride metabolites after exposure to different concentrations of 14C-vinyl chloride. In all of these experiments, including one of an exposure to only 2 ppm vinyl chloride, hepatic covalent protein binding was related to the dose of vinyl chloride which was actually metabolized, and the ratio between bound and metabolized material was constant. This strongly suggests that hepatic glutathione levels must have only a very limited impact on covalent protein binding of vinyl chloride metabolites, an assumption which is supported by a lacking effect of a pretreatment with diethylmaleate. A scheme of hepatocellular compartimentation of metabolic steps is proposed which serves to explain these findings.
氯乙烯和溴乙烯经肝脏微粒体酶代谢活化生成与蛋白质和核酸共价结合的中间体。有几条证据表明环氧化物参与其中，即氯环氧乙烷或溴环氧乙烷。已证实的烷基化靶点是核酸中的腺嘌呤、胞嘧啶和鸟嘌呤部分以及蛋白质的巯基。对于迄今为止研究的所有卤代乙烯，包括氯乙烯和溴乙烯，体内代谢是一个剂量依赖性的饱和过程。大鼠的代谢能力在氯乙烯大气浓度为250 ppm和溴乙烯为55 ppm时达到饱和。由于最近的报告描述了大鼠在暴露于50 ppm及以上氯乙烯浓度后肝细胞谷胱甘肽减少，我们进行了一系列实验，测量暴露于不同浓度14C-氯乙烯后氯乙烯代谢物的共价结合。在所有这些实验中，包括仅暴露于2 ppm氯乙烯的实验，肝脏共价蛋白结合与实际代谢的氯乙烯剂量相关，结合物与代谢物之间的比例是恒定的。这有力地表明肝脏谷胱甘肽水平对氯乙烯代谢物的共价蛋白结合的影响一定非常有限，这一假设得到了马来酸二乙酯预处理缺乏效果的支持。提出了一个肝细胞代谢步骤分隔的方案，用于解释这些发现。
