代谢
氯代和溴代卤代醋酸是饮用水消毒的副产品，也是啮齿动物的致癌物。氯溴二卤代醋酸还是基于机制的谷胱甘肽S-转移酶-zeta (GSTZ1-1) 抑制剂。本研究在雄性F344大鼠中研究了两种手性二卤代醋酸的立体特异性毒物动力学和体外代谢：(-)、(+)-溴氯醋酸 (BCA) 和非GST-zeta抑制的二卤代醋酸外消旋氯氟醋酸 (CFA)。这些实验在之前用二氯醋酸 (DCA) 处理过的动物中重复进行，以耗尽GST-zeta活性。结果表明，(-)-BCA的消除半衰期是0.07小时，而(+)-BCA在未经处理的大鼠中是0.40小时。CFA立体异构体也观察到了类似的消除半衰期差异（0.79 vs 0.11小时）。在GST-zeta耗尽的大鼠中，(-)、(+)-BCA的立体特异性消除消失，两种立体异构体的消除半衰期大约为0.4小时。这一发现与CFA的结果形成对比，CFA在其立体异构体之间仍然保持相同的相对消除速率差异，尽管在GST-zeta耗尽的大鼠中整体消除减弱。体外代谢实验的结果表明，(-)-BCA受到调节GST-zeta活性的影响，内在代谢清除率从2.81降低到0.15 mL/hr/mg蛋白质（未经处理，GST-zeta耗尽），而(+)-BCA的值分别为0.30和0.31 mL/hr/mg蛋白质。与350 uM二乙基二硫代氨基甲酸盐孵育优先降低未经处理和GST-zeta耗尽细胞溶胶中(+)-BCA的代谢。这些结果表明(+)-BCA是GST-zeta的差底物，其代谢受到另一种GST同工酶的控制。
The chloro- and bromohaloacetates are drinking water disinfection by-products and rodent carcinogens. Chloro-bromo dihaloacetates are also mechanism-based inhibitors of glutathione S-transferase-zeta (GSTZ1-1). ... The stereospecific toxicokinetics and in vitro metabolism of two chiral dihaloacetates /were studied/ in male F344 rats: (-),(+)-bromochloroacetate (BCA) and racemic chlorofluoroacetate (CFA), a non-GST-zeta-inhibiting dihaloacetate. These experiments were repeated in animals that had previously been treated with dichloroacetate (DCA) to deplete GST-zeta activity. Results indicated that the elimination half-life of (-)-BCA was 0.07 compared to 0.40 hr for (+)-BCA in naive rats. A comparable difference in elimination half-life was also observed for the CFA stereoisomers (0.79 vs 0.11 hr). In GST-zeta-depleted rats, stereospecific elimination of (-),(+)-BCA was absent, with both stereoisomers having an elimination half-life of approximately 0.4 hr. This finding was in contrast to results for CFA, which still maintained the same relative difference in elimination rate between its stereoisomers, although overall elimination was diminished in GST-zeta-depleted rats. Results of in vitro metabolism experiments indicated (-)-BCA was affected by modulating GST-zeta activity, with the intrinsic metabolic clearance decreasing from 2.81 to 0.15 mL/hr/mg protein (naive, GST-zeta depleted) compared with values for (+)-BCA (0.30 and 0.31 mL/hr/mg.protein). Incubations with 350 uM diethyldithiocarbamate preferentially decreased (+)-BCA metabolism in naive and GST-zeta-depleted cytosol. These results indicate (+)-BCA is a poor substrate for GST-zeta and its metabolism is controlled by an additional GST isoenzyme.
来源:Hazardous Substances Data Bank (HSDB)
