Gonzalez-Leon A, Merdink J L, Bull R J, Schultz I R
Pharmacology/Toxicology Graduate Program, Washington State University, Pullman, USA.
Chem Biol Interact. 1999 Dec 15;123(3):239-53. doi: 10.1016/s0009-2797(99)00140-4.
Dichloroacetate (DCA) and trichloroacetate (TCA) are prominent by-products of chlorination of drinking water. Both chemicals have been shown to be hepatic carcinogens in mice. Prior work has demonstrated that DCA inhibits its own metabolism in rats and humans. This study focuses on the effect of prior administration of DCA or TCA in drinking water on the pharmacokinetics of a subsequent challenge dose of DCA or TCA in male B6C3F1 mice. Mice were provided with DCA or TCA in their drinking water at 2 g/l for 14 days and then challenged with a 100 mg/kg i.v. (non-labeled) or gavage (14C-labeled) dose of DCA or TCA. The challenge dose was administered after 16 h fasting and removal of the haloacetate pre-treatment. The haloacetate blood concentration-time profile and the disposition of 14C were characterized and compared with controls. The effect of pre-treatment on the in vitro metabolism of DCA in hepatic S9 was also evaluated. Pre-treatment with DCA caused a significant increase in the blood concentration-time profiles of the challenge dose of DCA. No effect on the blood concentration-time profile of DCA was observed after pre-treatment with TCA. Pre-treatment with TCA had no effect on subsequent doses of DCA. Pre-treatment with DCA did not have a significant effect on the formation of 14CO2 from radiolabeled DCA. In vitro experiments with liver S9 from DCA-pre-treated mice demonstrated that DCA inhibits it own metabolism. These results indicate that DCA metabolism in mice is also susceptible to inhibition by prior treatment with DCA, however the impact on clearance is less marked in mice than in F344 rats. In contrast, the metabolism and pharmacokinetics of TCA is not affected by pre-treatment with either DCA or TCA.
二氯乙酸（DCA）和三氯乙酸（TCA）是饮用水氯化过程中产生的主要副产物。这两种化学物质已被证明是小鼠的肝脏致癌物。先前的研究表明，DCA会抑制其在大鼠和人类体内的代谢。本研究聚焦于在雄性B6C3F1小鼠饮用水中预先给予DCA或TCA对随后给予的DCA或TCA挑战剂量的药代动力学的影响。给小鼠提供浓度为2 g/l的含DCA或TCA的饮用水，持续14天，然后静脉注射（非标记）或灌胃（14C标记）100 mg/kg剂量的DCA或TCA进行挑战。在禁食16小时并去除卤乙酸预处理后给予挑战剂量。对卤乙酸血药浓度-时间曲线和14C的处置情况进行了表征，并与对照组进行了比较。还评估了预处理对肝S9中DCA体外代谢的影响。用DCA预处理导致DCA挑战剂量的血药浓度-时间曲线显著增加。用TCA预处理后未观察到对DCA血药浓度-时间曲线的影响。用TCA预处理对随后的DCA剂量没有影响。用DCA预处理对放射性标记的DCA形成14CO2没有显著影响。用来自DCA预处理小鼠的肝脏S9进行的体外实验表明，DCA会抑制其自身的代谢。这些结果表明，小鼠体内的DCA代谢也易受DCA预处理的抑制，但对清除率的影响在小鼠中不如在F344大鼠中明显。相比之下，TCA的代谢和药代动力学不受DCA或TCA预处理的影响。
