Studies On Change Of Anesthetics Metabolic Related Cytochrome P450sin Chronic Hepatic Diseases

The cytochrome P450 are the hemoprotein products of CYP multigene superfamily. They have important significance in pharmacology and toxicology which serve as the terminal oxidase in hepatic mixed-function oxidase systems, and play a major role in the detoxification of foreign compounds, includeing anesthetics and carcinogens. CYP2E1 and CYP3A4 are two important P450 isoenzymes which metabolize the volatile anesthetics and many intravenous anesthetics respectively. About 200 CYPs have been found in 10 years, and many factors including age, gender, nutrition, hormone and general or local pathologic reaction will affect CYPs, then the biotransformation of many clinical anesthetics will be changed. My objective is to compare the difference of CYP2E1 /3A4 enzyme and their gene expression between patients with hepatic cirrhosis and cholangetic jaundice , and to investigate the pharmacologic and clinical significance behind this difference.MethodsLiver samples were obtained from patients undergoing hepatic surgery with the hepatic cirrhosis(n=7) and cholangetic jaundice(n=6) and hepatic angioma (controls). Liver microsomes were prepared by ultracentrifugation, microsome proteins were measured by Lowry's method and total hepatic P450s were measured by differential spectrophotometry of CO. CYP3A4 activity and protein was determined by methods of Nash and Western blot respectively .Total RNA of liver were extracted using the one-step mothod,CYP2E1 and 3A4cDNA probe were prepared according method of random primer marking, and difference of these two genes expression were compared3among those patients by Northern blotting. Finally, We investigate the effect of propofol on CYP3A4 activity and protein express in primary culture hepatocytes.ResultsCompared to control group, the CYP3A4 activity and protein in liver tissue among patients with cirrhosis liver are evidently reduced, and the same change has been found in its gene express. CYP3A4 isoenzyme were unaltered among patients with cholangetic jaundice. Levels of cyp2e 1 and cyp3a4 mRNA among normal hepatic tissue are also high, but the gene expressions of cyp2e 1 in liver tissue among patients with jaundice are evidenfly reduced , in contrast, expression of this gene in cirrhosis liver were unalteredIn primary culture hepatocytes, We can find that clinical related concentration of prpopfol will reduce CYP3A4 activity , but only high concentration of propofol will reduce its protein.ConclusionP450 2E 1 /3A4 Isoenzyme and their Gene Expression have changed differently in Chronic Liver Disease. Among patients with hepatic cirrohisis , liver's ability of metabolism of intravenous anesthetics will reduced consequently as CYP3A4 reduced, and volatile anesthetics' biotransformation will also be affected among patients with cholangetic jaundice while CYP2E1 reduced, in some special conditions, even the biotransformation path of anesthetics will be changed. Finally, as clinical level concentration of propofol will reduce CYP3A4 activity , the metabolism rate of CYP3A4 substrate will be reduced, We should pay attention to the drug-drug interaction through pharmacokinetics and pharmacodynamics when We use different anesthetics during our clinical work.