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Identifying Cysteine, N-Acetylcysteine, and Glutathione Conjugates as Novel Metabolites of Aristolochic Acid I: Emergence of a New Detoxification Pathway.
Chemical Research in Toxicology ( IF 3.7 ) Pub Date : 2020-02-12 , DOI: 10.1021/acs.chemrestox.9b00488 Jiayin Zhang 1 , Chi-Kong Chan 1 , Yat-Hing Ham 1 , Wan Chan 1
Chemical Research in Toxicology ( IF 3.7 ) Pub Date : 2020-02-12 , DOI: 10.1021/acs.chemrestox.9b00488 Jiayin Zhang 1 , Chi-Kong Chan 1 , Yat-Hing Ham 1 , Wan Chan 1
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There is accumulating evidence that Balkan endemic nephropathy (BEN) is an environmental disease caused by aristolochic acids (AAs) released from the decomposition of Aristolochia clematitis L., an AA-containing weed that grows abundantly in the Balkan Peninsula. AA exposure has also been associated with carcinoma development in the upper urinary tract of some patients suffering from BEN. It is believed that an aristolactam-nitrenium ion intermediate with a delocalized positive charge produced in the hepatic metabolism of AAs binds to DNA and the resulting DNA adduct is responsible for initiating the carcinoma development process. In this study, we demonstrated for the first time that the aristolactam-nitrenium ion intermediate will also react with endogenous aminothiols, for example, cysteine, N-acetylcysteine, and glutathione in vitro, and in rats, producing phase II-conjugated metabolites in a dosage-dependent manner. It is highly possible that this conjugation process consumes and ultimately deactivates this carcinogenic intermediate and acts as an important, but previously unreported, detoxification mechanism of AAs. Results also showed AAs, phase I metabolites, and the aminothiol-conjugated metabolites are rapidly eliminated from AA-exposed rats. Furthermore, we found evidence that AA exposure induced oxidative stress in rats, as indicated by the glutathione depletion in rat serum samples.
中文翻译：
鉴定半胱氨酸，N-乙酰半胱氨酸和谷胱甘肽结合物为马兜铃酸的新型代谢物I：一种新的解毒途径的出现。
越来越多的证据表明，巴尔干地方性肾病（BEN）是由马兜铃菌L.分解而成的一种马兜铃酸（AAs）引起的环境疾病。马兜铃菌clematitis L.的杂草在巴尔干半岛上大量生长。AA暴露还与一些患有BEN的患者的上尿路癌形成有关。据信，在AA的肝代谢中产生的具有离域正电荷的马兜铃内酰胺-氮离子中间体与DNA结合，并且所得的DNA加合物负责启动癌的发展过程。在这项研究中，我们首次证明了马兜铃内酰胺-氮离子中间体也会与内源性氨基硫醇反应，例如半胱氨酸，N-乙酰半胱氨酸和谷胱甘肽在体外以及在大鼠中以剂量依赖性方式产生II期结合的代谢产物。这种结合过程很可能会消耗并最终使这种致癌中间物失活，并起着重要但以前未报道的AA排毒机制的作用。结果还显示，AA暴露的大鼠迅速消除了AA，I期代谢物和氨基硫醇结合的代谢物。此外，我们发现有证据表明，AA暴露可引起大鼠氧化应激，如大鼠血清样品中谷胱甘肽耗竭所表明的。
更新日期：2020-02-12
中文翻译：
鉴定半胱氨酸，N-乙酰半胱氨酸和谷胱甘肽结合物为马兜铃酸的新型代谢物I：一种新的解毒途径的出现。
越来越多的证据表明，巴尔干地方性肾病（BEN）是由马兜铃菌L.分解而成的一种马兜铃酸（AAs）引起的环境疾病。马兜铃菌clematitis L.的杂草在巴尔干半岛上大量生长。AA暴露还与一些患有BEN的患者的上尿路癌形成有关。据信，在AA的肝代谢中产生的具有离域正电荷的马兜铃内酰胺-氮离子中间体与DNA结合，并且所得的DNA加合物负责启动癌的发展过程。在这项研究中，我们首次证明了马兜铃内酰胺-氮离子中间体也会与内源性氨基硫醇反应，例如半胱氨酸，N-乙酰半胱氨酸和谷胱甘肽在体外以及在大鼠中以剂量依赖性方式产生II期结合的代谢产物。这种结合过程很可能会消耗并最终使这种致癌中间物失活，并起着重要但以前未报道的AA排毒机制的作用。结果还显示，AA暴露的大鼠迅速消除了AA，I期代谢物和氨基硫醇结合的代谢物。此外，我们发现有证据表明，AA暴露可引起大鼠氧化应激，如大鼠血清样品中谷胱甘肽耗竭所表明的。
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