Soni M G, Mangipudy R S, Mumtaz M M, Mehendale H M
Division of Toxicology, College of Pharmacy and Health Sciences, Northeast Louisiana University, Monroe 71209-0470, USA.
Toxicol Sci. 1998 Apr;42(2):158-65. doi: 10.1006/toxs.1998.2427.
Trichloroethylene (TCE), a widely used organic solvent and degreasing agent, is regarded as a hepatotoxicant. The objective of the present studies was to investigate whether the extent and timeliness of tissue repair has a determining influence on the ultimate outcome of hepatotoxicity. Male Sprague-Dawley rats (200-250 g) were injected with a 10-fold dose range of TCE and hepatotoxicity and tissue repair were studied during a time course of 0 to 96 h. Light microscopic changes as evaluated by H&E-stained liver sections revealed a dose-dependent necrosis of hepatic cells. Maximum liver cell necrosis was observed at 48 h after the TCE administration. However, liver injury as assessed by plasma sorbitol dehydrogenase (SDH) showed a dose response over a 10-fold dose range only at 6 h, whereas alanine aminotransferase (ALT) did not show a dose response at any of the time points studied. A low dose of TCE (250 mg/kg) showed an increase in SDH at all time points up to 96 h without peak levels, whereas higher doses showed peak only at 6 h. At later time points SDH declined but remained above normal. In vitro addition of trichloroacetic acid, a metabolite of TCE to plasma, decreased the activities of SDH and ALT indicating that metabolites formed during TCE toxicity may interfere with plasma enzyme activities in vivo. This indicates that the lack of dose-related increase in SDH and ALT activities may be because of interference by the TCE metabolite. Tissue regeneration response as measured by [3H]thymidine incorporation into hepatocellular nuclear DNA was stimulated maximally at 24 h after 500 mg/kg TCE administration. A higher dose of TCE led to a delay and diminishment in [3H]thymidine incorporation. At a low dose of TCE (250 mg/kg) [3H]thymidine incorporation peaked at 48 h and this could be attributed to very low or minimal injury caused by this dose. With higher doses tissue repair was delayed and attenuated allowing for unrestrained progression of liver injury. These results support the concept that the toxicity and repair are opposing responses and that a dose-related increase in tissue repair represents a dynamic, quantifiable compensatory mechanism.
三氯乙烯（TCE）是一种广泛使用的有机溶剂和脱脂剂，被视为一种肝毒物。本研究的目的是调查组织修复的程度和及时性是否对肝毒性的最终结果具有决定性影响。将体重200 - 250克的雄性Sprague-Dawley大鼠注射10倍剂量范围的TCE，并在0至96小时的时间进程中研究肝毒性和组织修复情况。通过苏木精和伊红（H&E）染色的肝脏切片评估的光镜变化显示肝细胞呈剂量依赖性坏死。在给予TCE后48小时观察到最大程度的肝细胞坏死。然而，通过血浆山梨醇脱氢酶（SDH）评估的肝损伤仅在6小时时在10倍剂量范围内呈现剂量反应，而丙氨酸氨基转移酶（ALT）在研究的任何时间点均未显示剂量反应。低剂量的TCE（250毫克/千克）在直至96小时的所有时间点均显示SDH升高且无峰值水平，而较高剂量仅在6小时时出现峰值。在随后的时间点，SDH下降但仍高于正常水平。在体外将TCE的代谢产物三氯乙酸添加到血浆中，会降低SDH和ALT的活性，这表明TCE毒性过程中形成的代谢产物可能在体内干扰血浆酶活性。这表明SDH和ALT活性缺乏剂量相关的增加可能是由于TCE代谢产物的干扰。通过将[³H]胸腺嘧啶掺入肝细胞核DNA来测量的组织再生反应在给予500毫克/千克TCE后24小时受到最大刺激。更高剂量的TCE导致[³H]胸腺嘧啶掺入延迟和减少。在低剂量的TCE（250毫克/千克）下，[³H]胸腺嘧啶掺入在48小时达到峰值，这可归因于该剂量引起的极低或最小损伤。随着剂量增加，组织修复延迟且减弱，从而使肝损伤不受控制地进展。这些结果支持这样的概念，即毒性和修复是相反反应，并且组织修复的剂量相关增加代表一种动态、可量化的补偿机制。
