Templin M V, Parker J C, Bull R J
Pharmacology/Toxicology Graduate Program, College of Pharmacy, Washington State University, Pullman 99164-6510.
Toxicol Appl Pharmacol. 1993 Nov;123(1):1-8. doi: 10.1006/taap.1993.1214.
The hepatocarcinogenicity of trichloroethylene (TRI) has been attributed to the metabolite trichloroacetate (TCA). However, mice also form dichloroacetate (DCA) and trichloroethanol (TCE) as metabolites of TRI. TCA and DCA have both been shown to induce hepatic tumors in mice. This study was undertaken to measure the kinetics of TCA and DCA formation in the B6C3F1 mouse using doses of TRI ranging from 0.38 to 15 mmol/kg and TCA at doses of 0.03 to 0.61 mmol/kg. The formation and elimination of TCA and DCA have been found to be nonlinear with the dose of TRI. Quantifiable levels of DCA were found in blood with doses above 0.76 mmol/kg TRI. The peak concentration of DCA did not show an appreciable change with an increased dose; however, the area under the curve (AUC) increased linearly with respect to the dose of TRI. Both peak concentration and AUC of TCA and TCE increased in a linear manner to a dose of 3.8 mmol/kg. The kinetics of TCA elimination following doses of TCA were similar to those found for TCA following doses of TRI. A significant dose-dependent partitioning of TCA into blood over liver was found at the higher doses of TRI and TCA investigated. Binding of TCA to plasma constituents accounted for this distributional pattern. Prior work has documented that DCA can be formed from TCA. However, the AUC for DCA following TRI exceeds that predicted from the formation of TCA from TRI. Additional pathways would, therefore, appear to account for the formation of DCA. Results from this investigation suggest that sufficient concentrations of DCA appear to be formed and may contribute to the hepatocarcinogenicity of TRI.
三氯乙烯（TRI）的肝致癌性被认为归因于其代谢产物三氯乙酸（TCA）。然而，小鼠也会将二氯乙酸（DCA）和三氯乙醇（TCE）作为TRI的代谢产物形成。TCA和DCA均已被证明可在小鼠中诱发肝肿瘤。本研究旨在使用0.38至15 mmol/kg的TRI剂量以及0.03至0.61 mmol/kg的TCA剂量来测量B6C3F1小鼠中TCA和DCA的形成动力学。已发现TCA和DCA的形成与消除与TRI剂量呈非线性关系。当TRI剂量高于0.76 mmol/kg时，在血液中发现了可量化水平的DCA。DCA的峰值浓度并未随剂量增加而出现明显变化；然而，曲线下面积（AUC）随TRI剂量呈线性增加。TCA和TCE的峰值浓度和AUC在剂量达到3.8 mmol/kg时均呈线性增加。TCA给药后TCA的消除动力学与TRI给药后TCA的消除动力学相似。在研究的较高剂量的TRI和TCA下，发现TCA在血液与肝脏之间存在显著的剂量依赖性分配。TCA与血浆成分的结合解释了这种分布模式。先前的研究记录了DCA可由TCA形成。然而，TRI给药后DCA的AUC超过了由TRI形成TCA所预测的值。因此，似乎有其他途径可解释DCA的形成。本研究结果表明，似乎会形成足够浓度的DCA，并且可能导致TRI的肝致癌性。
