Mourelle M, Meza M A
Pharmacology and Toxicology Department, CINVESTAV-IPN, México.
J Appl Toxicol. 1990 Feb;10(1):23-7. doi: 10.1002/jat.2550100105.
Loss of calcium regulation across the plasma membrane of hepatocytes is responsible for irreversible cell damage by CCl4. The mode of action of colchicine in CCl4 acute liver damage is not completely understood. We followed the time courses of the changes in lipoperoxidation, the activities of liver plasma membrane Ca2(+)-ATPase, gamma-glutamyl transpeptidase and alkaline phosphatase, as well as the time courses of serum markers of liver damage in rats acutely intoxicated with CCl4. We assessed the effects of colchicine in this model and evaluated the effect of this drug on liver cytochrome P-450. Increased lipoperoxidation is the earliest and shortest lasting effect of CCl4 in the liver and is followed by a decrease in the activities of plasma membrane-bound enzymes. The alterations in serum enzymes showed a slower onset and were more protracted. Colchicine pretreatment produced a small decrease in cytochrome P-450 in the liver but completely prevented most of the changes produced by CCl4 in lipoperoxidation, liver plasma membrane enzyme activities and serum enzyme activities. We conclude that CCl4 metabolites trigger lipoperoxidation and then produce a longer lasting change in the plasma membrane, which thus allows calcium accumulation. Colchicine prevents the early mechanisms of CCl4 damage, and its effect on cytochrome P-450 perhaps plays only a contributory role.
肝细胞质膜钙调节功能丧失是四氯化碳所致不可逆细胞损伤的原因。秋水仙碱在四氯化碳急性肝损伤中的作用方式尚未完全明确。我们跟踪了四氯化碳急性中毒大鼠的脂质过氧化、肝质膜Ca2(+)-ATP酶、γ-谷氨酰转肽酶和碱性磷酸酶活性变化的时间进程，以及肝损伤血清标志物的时间进程。我们评估了秋水仙碱在该模型中的作用，并评价了该药对肝细胞色素P-450的影响。脂质过氧化增加是四氯化碳在肝脏中最早出现且持续时间最短的效应，随后是质膜结合酶活性降低。血清酶的改变出现较晚且持续时间更长。秋水仙碱预处理使肝脏中的细胞色素P-450略有降低，但完全阻止了四氯化碳在脂质过氧化、肝质膜酶活性和血清酶活性方面产生的大部分变化。我们得出结论，四氯化碳代谢产物引发脂质过氧化，进而在质膜上产生更持久的变化，从而导致钙蓄积。秋水仙碱可预防四氯化碳损伤的早期机制，其对细胞色素P-450的作用可能仅起辅助作用。
