Gao P, Thornton-Manning J R, Pegram R A
ManTech Environmental Technology, Inc., Research Triangle Park, North Carolina 27711, USA.
J Toxicol Environ Health. 1996 Oct 11;49(2):145-59. doi: 10.1080/009841096160899.
Bromodichloromethane (BDCM), a carcinogenic water disinfection by-product, has been shown to be metabolized to intermediates that covalently bind to lipids and proteins, and this binding has been associated with trihalomethane-induced renal and hepatic toxicity. In this study, the effects of glutathione (GSH) on in vivo BDCM toxicity and in vitro BDCM macromolecular binding were evaluated. The in vivo toxicity of BDCM in animals pretreated with buthionine sulfoximine (BSO, a glutathione synthesis inhibitor) and in untreated male Fischer 344 rats was investigated. In another experiment, covalent binding to protein and lipid was quantified after [14C]BDCM was incubated with hepatic microsomal and S9 fractions and renal microsomes from F344 rats, under aerobic and anaerobic conditions, with and without added GSH. After oral dosing with BDCM, the BSO-pretreated animals had greatly increased levels of serum indicators of hepatotoxicity and serum and urinary indicators of nephrotoxicity compared to those in animals dosed solely with BDCM. Histopathological examination revealed that hepatic necrosis was more severe than renal necrosis in the BSO-treated rats. When GSH was added to an aerobic incubation, protein binding was decreased in hepatic microsomal and S9 fractions by 92 and 83%, respectively. GSH also decreased lipid binding by 55% in hepatic microsomal incubations carried out under anaerobic conditions. Addition of GSH decreased renal microsomal protein (aerobic) and lipid binding (anaerobic) by 20 and 43%, respectively. These data indicate that GSH is an important protective factor in the toxicity associated with BDCM.
溴二氯甲烷（BDCM）是一种具有致癌性的水消毒副产物，已被证明可代谢为与脂质和蛋白质共价结合的中间体，这种结合与三卤甲烷诱导的肾毒性和肝毒性有关。在本研究中，评估了谷胱甘肽（GSH）对体内BDCM毒性和体外BDCM大分子结合的影响。研究了用丁硫氨酸亚砜胺（BSO，一种谷胱甘肽合成抑制剂）预处理的动物以及未处理的雄性Fischer 344大鼠体内BDCM的毒性。在另一项实验中，在有氧和无氧条件下，在添加和不添加GSH的情况下，将[14C]BDCM与F344大鼠的肝微粒体、S9组分和肾微粒体一起孵育后，对蛋白质和脂质的共价结合进行了定量。口服BDCM后，与仅给予BDCM的动物相比，经BSO预处理的动物肝毒性血清指标以及肾毒性血清和尿液指标水平大幅升高。组织病理学检查显示，经BSO处理的大鼠肝坏死比肾坏死更严重。当在有氧孵育中添加GSH时，肝微粒体和S9组分中的蛋白质结合分别减少了92%和83%。在厌氧条件下进行的肝微粒体孵育中，GSH还使脂质结合减少了55%。添加GSH分别使肾微粒体蛋白质（有氧）和脂质结合（厌氧）减少了20%和43%。这些数据表明，GSH是与BDCM相关毒性中的一个重要保护因子。
