Study Of MRNA Expression Of Hepatic Phase Ⅱ Enzymes Related To Anesthetic Metabolism UGT1A1, 1A6, 2B1 In Rats With Obstructive Jaundice

Research background and objective:Phase II drug-metabolizing reaction play a critical role in drugbiotransformation. UDP-glucuronosyltransferases (UGTs), one of major enzymes of phase II reaction in human, catalyze the conjugation on a wide range of endogeous and exogenous chemicals using UDP-glucuronic acid(UDPGA)as the sugar donor, increase the polarity and facilitate their excretion. Like the CYP450s, the genes of UGTs belong to a superfamily, and are divided into two gene family:UGTl and UGT2. UGT1A1, 1A6,2B1 are isozymes related to the metabolism of clinical anesthetic, in charge of catalyzing the respective phase II conjugating reaction of the commonly used anesthetic: morphine, naloxone, nalorphine, naltrexone, propofol and haloperidol.Obstructive jaundice(OJ) is a common symptom of clinical hepatobiliary diseases, chiefly caused by bile duct obstruction. In the recent year, some scholars have performed a lot of studies about mechanism of liver injury, change of pathobiology and CYPs of phase I in cirrhosis and hepatitis.But there is few detailed report about the change of hepatic function, pathomorphology and the phase II metabolic enzymes in the different phase of OJ. Our objective is to establish the OJ rat model, observe the change of liver functional indices, pathomorphology and detect the mRNA expression of UGT1A1, 1A6,2B1 in liver, further to explore the change of anesthetic-metabolic mechanism in OJ .METHODS:1. To establish the OJ rat model by bile duct ligation,observe thechange of liver functional indices and pathomorphology in the different phase.2. To detect the mRNA expression quantity of UGT1A1, 1A6,2B1 in liver by real-time fluorescence quantitative RT-PCR in the different OJ phase.Results:1. Part I, the hepatic tissue evolves gradually after the obstruction of biliary duct, and the typical change of pathomorphology is bile duct proliferation and hepatic fibrosis. There is a similar variation between the serum TBIL, DBIL, TBA values and biochemical indices ALT, AST, ALP, GGT in the phase of OJ. The values reach the peak in the early phase (BDL:! or BDL7) and decrease gradually, but in the end stage (BDL42), they are still higher than those of the control group . The value of serum TP has a distinguished decrease following with the prolongation of obstruction.2. Part II, in the early phase of OJ rats, there is a significant increase of the mRNA expression of UGT1A1, 1A6, 2B1 in liver . In the group of BDL3 and BDL7) the expression quantity of UGT1A1, 1A6, 2BlmRNA are 2-3 times higher than that in the control group. As OJ persists, the mRNA expression of three isozymes falls down significantly. In the end stage of experiment (BDL28) , the mRNA expression of UGT1A6 is lower than that of the control group,but UGT1A1 and 2B1 remains higher.Conclusion:l.The bile duct obstruction caused the obvious impairment of liver function and pathomorphology in OJ. The organism can compensate to decrease the high level TBIL and TBA, revert liver functional indices to some degree as OJ appears. But if the obstruction is unable to relieve, the prolongation of OJ will make hepatocyte denatured and necrosis, and lead to irreversible cirrhosis finally.2.There is similar tendency between the change of serum TBIL,DBIL, TBA values and mRNA expression of UGT1A1, 1A6, 2B1 in liver of OJ ratsrall the values- reach the peak in the early phase ,then fall down gradually. We infered: 1, the accumulation of endogenous substrates such as high level...