Toxopeus C, Frazier J M
Department of Pharmacology and Toxicology, Wright State University, Dayton, Ohio 45435, USA.
Toxicol Appl Pharmacol. 1998 Sep;152(1):90-8. doi: 10.1006/taap.1998.8505.
Trichloroacetic acid (TCA) and dichloroacetic acid (DCA) are environmental contaminants that are suspected human carcinogens. To obtain more detail on the role of the liver in the kinetics of TCA and DCA, experimental studies in the isolated perfused rat liver (IPRL) system were conducted. The IPRL system was dosed with either 5 or 50 micromol of either TCA or DCA (25 or 250 microM initial concentration, respectively). TCA and DCA concentrations were followed in perfusion medium and bile for 2 h. The chemical concentration in liver was determined at the end of exposure. Liver viability was monitored by measuring leakage of lactate dehydrogenase (LDH) into perfusion medium and the rate of bile production. Studies performed with TCA showed that the total TCA concentration in perfusion medium decreased slightly during the first 30 min of exposure and remained constant thereafter. Most TCA, greater than 90% of total, was bound to albumin in the perfusion medium. A low, linear excretion rate of TCA in bile was obtained. The calculated free TCA concentration in the liver intracellular water space was higher than the unbound TCA concentration in the perfusion medium. Parallel studies with DCA showed that the DCA concentration in perfusion medium decreased rapidly. Of the total DCA in the perfusion medium, 60% was bound to albumin. The concentration of DCA in bile decreased over time. There was no DCA detectable in the liver after 2 h of exposure at both DCA concentrations. Enzyme leakage and bile production did not change in the presence of TCA or DCA, indicating that these concentrations were not acutely cytotoxic to the liver.
三氯乙酸（TCA）和二氯乙酸（DCA）是环境污染物，被怀疑是人类致癌物。为了更详细地了解肝脏在TCA和DCA动力学中的作用，我们在离体灌注大鼠肝脏（IPRL）系统中进行了实验研究。IPRL系统分别给予5或50微摩尔的TCA或DCA（初始浓度分别为25或250微摩尔/升）。在灌注培养基和胆汁中跟踪TCA和DCA的浓度2小时。在暴露结束时测定肝脏中的化学物质浓度。通过测量乳酸脱氢酶（LDH）泄漏到灌注培养基中的情况和胆汁生成速率来监测肝脏活力。用TCA进行的研究表明，在暴露的前30分钟内，灌注培养基中TCA的总浓度略有下降，此后保持恒定。大部分TCA（超过总量的90%）与灌注培养基中的白蛋白结合。在胆汁中获得了较低的、线性的TCA排泄率。计算得出的肝脏细胞内水空间中的游离TCA浓度高于灌注培养基中未结合的TCA浓度。用DCA进行的平行研究表明，灌注培养基中DCA的浓度迅速下降。在灌注培养基中的总DCA中，60%与白蛋白结合。胆汁中DCA的浓度随时间下降。在两种DCA浓度下暴露2小时后，肝脏中未检测到DCA。在存在TCA或DCA的情况下，酶泄漏和胆汁生成没有变化，这表明这些浓度对肝脏没有急性细胞毒性。
