Changes Of Drug-Metabolizing Functions Of Liver And Small Intestine In Hepatic Fibrosis In Rats

The changs of xenobiotic (including drugs) chemical structures occuring in the body are called biotransformation. The liver is the major site of drug biotransformation, and the small intestine is the second site of that. The process of biotransformation involves two phases. Phase I reactions include oxidation, reduction and hydrolysis, these reactions introduce or expose a functional group (eg. glucuronic acid, sulfuric acid, aminoacetic acid, glutathione) which increases the polarity of the drug molecule and provides a site for phase II reactions; phase II reactions involve conjugation, the attachment of a large chemical group (eg. hydroxy, carboxyl, mercapto, amino) to a functional group in the drug molecule by means of covalent bond, conjugation results in the drug being more hydrophilic and thus more easily excreted from the body.Drug biotransformation is catalyzed by enzymes. Cytochrome P450 (CYP) 1-3 families are the prominent phase I metabolizing enzymes; uridine diphosphate-glucuronate transferase (UGT), glutathione S-transferase (GST) are the major enzymes in the reactions of phase II conjugation. Phase I and phase II metabolizing enzymes have the characters of large individual variability, easily induced or inhibited. To study the CYP isoforms responsible for drug metabolism in disease status, might be used to predict the theraputic effacy of drugs and drug to drug interactions, thus guide clinical reasonable medication; to study the CYP isoforms responsible for the metabolism and activation of procarcinogens and propoisons in disease status, might have important clinical significance of relieveing liver and intestine toxicity, preventing and curing tumor.We studyed the changes of drug-metabolizing functions of liver and small intestine in hepatic fibrosis in rats:To investigate the changes of drug-metabolizing function of liver in hepatic fibrosis to provide support for clinical reasonable medication in hepatic fibrosis patients. Carbon tetrachloride (CCU) and other mixture factors were used to make animal model of acute hepatic injury, hepatic fibrosis and cirrhosis, respectively. Microsomal drug-metabolizing enzymes and cytosol antioxidative enzymes were measured in the liver of hepatic fibrosisrats and compared with those of acute hepatic injury and hepatic cirrhosis rats. The results showed that, in hepatic fibrosis, levels of phase I enzymes-CYP content, 7-ethoxyresorufm O-deethylase (CYP1A1), aniline hydroxylase (CYP2E1), erythromycin TV-demethylase (CYP3A), and phase II enzymes-GST activities decreased remarkably, and were 41%, 68%, 56%, 81% and 59%, respectively, in comparison with those in control group; in acute hepatic injury, CYP2E1 activity reduced to the lowest, the rest indexs above reduced obiviously but the extents of reduction were lighter than those in hepatic fibrosis; in hepatic cirrhosis, CYP2E1 acitivity recoverd a little more, and the rest indexs above reduced further, in comparison with those in hepatic fibrosis. All of cytosol antioxidative enzymes-GST and catalase (Cat) acitivities decreased in the three statuses. The results indicated that in hepatic fibrosis, drug-metabolizing function of liver decreased, which constantly relates with the degrees and the lengths of hepatic injury.To investigate the changes of drug-metabolizing function of small intestinal mucosal epithelial cells in hepatic fibrosis. Drug-metabolizing enzymes, antioxidative enzymes and membrane fluidity of small intestinal mucosal epithelial cells were measured in hepatic fibrosis rats and compared with those in acute hepatic injury and hepatic cirrhosis rats. The results showed that the activities of phase I enzymes - CYP3A, CYP1A1 and aniline hydroxylase (CYP2E1) of small intestinal mucosal epithelial cells enhanced 2.2-, 0.6- and 0.3-times respectively, in comparison with control group, however, the activities of phase II enzymes-UDPGT, a-GST, Ti-GST decreased 15%, 43% and 57% respectively. Meanwhile, the content of membrane malondialdehyde (MDA) increased, and the activities of antioxidative enz...