慢性肝胆疾患P450同工酶CYP3A4表达的改变

Change of P450 isoenzyme CYP3A4 expression in different chronic liver diseases

目的：研究肝硬化和黄疸患者肝脏中CYP3A4蛋白含量、活性及其mRNA表达，进一步探讨其药理学意义。方法：提取肝炎后肝硬化、阻塞性黄疽及肝血管瘤患者的肝组织标本，以后者为正常肝组织对照；Nash法测定CYP3A4酶活性，ELISA法测定蛋白量，一步法抽提肝组织总 RNA，随机引物标记法制备 CYP3A4 cDNA探针，Northern杂交比较 CYP3A4基因在以上三组中的表达差异。结果：肝炎后肝硬化患者 CYP3A4蛋白量、活性及 mRNA表达较正常肝显著降低（P＜0．01），而阻塞性黄疽患者该酶改变与正常肝相差无显著性。结论：肝硬化患者 CYP3A4 mRNA表达显著降低，导致同工酶含量和酶活性下降，肝脏对包括静脉麻醉药物在内的多种药物的代谢能力下降，提示临床麻醉工作中应考虑药酶改变，减低患者的麻醉药剂量。

Objective: To study the CYP3A4 enzyme and its gene expression between patients with hepatic cirrhosis andcholangetic jaundice,and to investigate the pharmacologic significance behind this difference. Methods: Liver samples wereobtained from patients undergoing hepatic surgery with hepatic cirrhosis (n=7), cholangetic jaundice (n=6) and hepatic an-gioma (controls,n=6). CYP3A4 activity and protein was determined by Nash and ELISA respectively. Total hepatic RNAwere extracted using the one-step method, CYP3A4 cDNA probe were prepared through random primer marking, and differ-ence of CYP3A4 expression were compared among those patients by Northern blotting. Results: Compared to control group,the CYP3A4 activity and protein in liver tissue among patients with cirrhosis were evidently reduced(P<0. 01), and northernblot showed the same change about its mRNA levels. In contrast, the isoenzyme was unaltered among patients withcholangetic jaundice. Conclusion: CYP3A4 isoenzyme amount and its activity decline in patients with hepatic cirrhosis as ex-pression of CYP3A4 mRNA are significantly reduced. Liver function of substrate metabolism including intravenous anesthet-ics declines consequently, the anesthetic dosage should be reduced among patients with hepatic diseases in accordance withisoenzyme change.