Rao S B, Young R A, Mehendale H M
Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson 39216-4505.
J Biochem Toxicol. 1990 Spring;5(1):23-32. doi: 10.1002/jbt.2570050105.
The mechanism by which chlordecone (CD) amplifies the hepatotoxicity of halomethanes such as CCl4, CHCl3, and BrCCl3 has been a subject of intense study. Recent work has shown that suppression of hepatocellular regeneration leads to accelerated progression of liver injury leading to complete hepatic failure due to an unusual interaction between individually nontoxic low-dose combination of CD and CCl4. Since polyamines are involved in cell division, their levels reflect the extent to which there is suppression of hepatocellular regeneration during CD and CCl4 interaction. The present studies were designed to investigate the polyamine levels and associated enzymes in livers of rats treated with BrCCl3 alone or CD and BrCCl3 low-dose combination in order to confirm whether the sequence of events of hepatotoxicity is similar to that seen in CCl4 toxicity or that seen during CD and CCl4 interaction. The extent of liver toxicity in rats fed 10 ppm chlordecone (CD) for 15 days prior to the injection of a single low dose of BrCCl3 (15 microL/kg body weight) or after exposure to a high dose of BrCCl3 (80 microL/kg body weight) without CD pretreatment, was similar 6 and 24 hr later as assessed by plasma transaminase levels. There was also an increase in transaminase levels, in rats exposed to a single low dose of BrCCl3 alone (15 microL/kg body weight) but this increase was far below the high-dose exposure alone or the combination treatment. Hepatic levels of ornithine decarboxylase, S-adenosylmethionine decarboxylase, N1-acetylputrescine, N1-acetylspermidine, putrescine, spermidine, and spermine at the end of 24 hr increased after exposure to a low dose of BrCCl3 alone as compared to exposure to a high dose alone or the low-dose combination of CD and BrCCl3. Liver spermidine N1-acetyltransferase was elevated at 2, 6, and 24 hr after exposure to a high dose of BrCCl3 alone as compared to treatment with a low-dose combination of CD and BrCCl3 suggesting decreased synthesis of this enzyme, in spite of a greater need as seen from liver transaminase levels. In general, it was observed that there is significant elevation in some polyamines and related enzymes during toxicity of a low dose of BrCCl3 which seemed to stabilize within 24 hr. This was not observed with the other two groups of rats exposed either to BrCCl3 high dose alone or the low-dose combination of CD and BrCCl3.(ABSTRACT TRUNCATED AT 400 WORDS)
开蓬（CD）增强四氯化碳、氯仿和三氯溴甲烷等卤代甲烷肝毒性的机制一直是深入研究的课题。最近的研究表明，肝细胞再生的抑制会导致肝损伤加速进展，由于CD和CCl4单独无毒的低剂量组合之间存在异常相互作用，最终导致完全肝衰竭。由于多胺参与细胞分裂，它们的水平反映了CD和CCl4相互作用期间肝细胞再生受抑制的程度。本研究旨在调查单独用三氯溴甲烷或CD与三氯溴甲烷低剂量组合处理的大鼠肝脏中的多胺水平及相关酶，以确认肝毒性事件的顺序是否与CCl4毒性中所见的相似，或与CD和CCl4相互作用期间所见的相似。在注射单次低剂量三氯溴甲烷（15微升/千克体重）之前或在未进行CD预处理而暴露于高剂量三氯溴甲烷（80微升/千克体重）之后，给大鼠喂食10 ppm开蓬（CD）15天，6小时和24小时后通过血浆转氨酶水平评估，肝脏毒性程度相似。单独暴露于单次低剂量三氯溴甲烷（15微升/千克体重）的大鼠转氨酶水平也有所升高，但这种升高远低于单独高剂量暴露或联合治疗。与单独高剂量暴露或CD与三氯溴甲烷低剂量组合相比，单独暴露于低剂量三氯溴甲烷24小时后，肝脏中的鸟氨酸脱羧酶、S-腺苷甲硫氨酸脱羧酶、N1-乙酰腐胺、N1-乙酰亚精胺、腐胺、亚精胺和精胺水平升高。与CD和三氯溴甲烷低剂量组合治疗相比，单独暴露于高剂量三氯溴甲烷后2、6和24小时肝脏亚精胺N1-乙酰转移酶升高，这表明尽管从肝脏转氨酶水平来看有更大需求，但该酶的合成减少。总体而言，观察到在低剂量三氯溴甲烷毒性期间某些多胺和相关酶有显著升高，且似乎在24小时内稳定下来。单独暴露于高剂量三氯溴甲烷或CD与三氯溴甲烷低剂量组合的其他两组大鼠未观察到这种情况。（摘要截短至400字）
