肝损伤大鼠肝脏异物代谢功能的改变

目的　研究不同肝损伤状态下肝脏药物代谢和抗氧化功能的变化及规律 ,为肝纤维化患者的临床合理用药提供依据。方法　建立大鼠四氯化碳急性肝损伤和复合因素肝纤维化、肝硬化模型 ,差速离心法制备肝亚细胞组分 ,测定药物代谢酶和抗氧化酶活性。结果　不同肝损伤状态下大鼠肝微粒体药物代谢Ⅰ相酶———细胞色素P4 5 0 (CYP)总量、CYP1A1、3A活性和Ⅱ相酶—谷胱甘肽S 转移酶 (GST)活性均明显降低 ,随损伤时间递减 ,在肝硬化时达最低 ;而CYP2E1活性在急性肝损伤时即达最低 ,随染毒时间的延长而有所恢复。肝纤维化状态下CYP1A、CYP2E1、CYP3A和GST活性分别为正常对照组的 6 8%、5 6 %、81%和 5 9%。肝纤维化状态下胞浆抗氧化酶 GST、过氧化氢酶和谷胱甘肽过氧化物酶活性也呈不同程度降低 ,为正常对照组的 85 %、76 %和 5 4 %。结论　肝纤维化时 ,肝脏异物代谢酶功能降低 ,其降低程度多与肝损伤轻重和时间长短有关。

Changes of liver xenobiotic-metabolizing function at different status of hepatic injury

Aim The changes and characteristics of liver drug-metabolizing and antioxiditive functions in different status of hepatic injury was investigated to provide support for clinical drug treatments in hepatic fibrosis. Methods Carbon tetrachloride (CCl 4) and other mixture factors were used to make animal model of acute hepatic injury, hepatic fibrosis and cirrhosis, respectively. Subcelluar fractions of liver were prepared by differential centrifugation. Activities of drug-metabolizing and antioxidative enzymes were monitored. Results Levels of phase I enzymes-cytochrome P450 (CYP), CYP1A1 (7-ethoxyresorufin O-deethylation), CYP2E1 (aniline hydroxylation), CYP3A1/2 (erythromycin N-demethylation), and phase Ⅱ enzymes-glutathione S-transferase (GST) were reduced remarkably in hepatic microsomes in different hepatic injury status in a time-dependent manner. However, the activity of CYP2E1 came to be the lowest in acute hepatic injury and recovered gradually when injury time was prolonged. In hepatic fibrosis, the activities of CYP1A,CYP2E1,CYP3A and GST reached 68%,56%,81% and 59%, respectively, of the control, and the functions of antioxidative enzymes in cytosol GST,catalase(Cat) and glutathione peroxidase(GSH-Px) declined to 85%,76% and 54%, respectively, of the control. Conclusion The xenobiotic-metabolizing abilities in liver with hepatic fibrosis were distinctly decreased, which constantly relates with the degrees and the lengths of hepatic injury.