Correction of dysfunction of enzyme systems of microsomal oxidation, glucuronidation, and glutathione conjugation of xenobiotics in the liver of rats with deoxycholate intoxication

Abstract

Intoxication with deoxycholic acid disturbed the integrity of hepatocyte plasma membranes (elevation of alanine transaminase activity in the plasma) and inhibited the monooxygenase, glucuronosyltransferase, and glutathione S-transferase systems in rat liver. Heptral and cordiaminum did not affect the integrity of plasma membranes, while ~-tocopherol and, especially, ursofalk produced membrane-protective effects. Ursofalk and, especially, cordiaminum are far superior to (~-tocopherol and heptral in their ability to normalize functions of the monooxygenase, glucuronosyltransferase, and glutathione S-transferase systems in rat liver. Key Words: deoxycholic acid-induced liver damage; biotransformation of xenobiotics: heptral; cordiaminum; ursofalk: o~-tocopherolThe blood of animals and humans with cholestasis contains considerable amounts of cholates, other bile components, and intermediate products of impaired metabolism and. therefore, is toxic to the body. Endotoxemia m cholestasis leads to liver dysfunction and impairs biotransformation of drugs and other xenobiotics. This promotes their accumulation in the body and aggravates intoxication. Experiments on animals showed that hydrophobic fatty acids play the major role in the pathogenesis of hepatotoxicity during cholestasis [ 12].Here we studied disturbances in xenobiotic transformation in the liver during deoxycholic acid (DCA) intoxication. Heptral. (~-tocopherol, ursofalk, and cordiaminum were used to correct metabolic dysfunction. MATERIALS AND METHODSExperiments were performed on 62 male rats weighing 200-240 g. DCA was administered through a gastric tube (i.g., 250 mg/kg/day in starch slurry) for 8 days. Heptral (100 mg/kg), cordiaminum (50 mg/kg), and vitamin E (50 mg/kg) were injected intraperitoneally (i.p.); ursofalk was administered i.g. (100 mg/kg/day in the starch slurry). Control rats received equivalent amounts of DCA or starch slurry (i.g.) and 0.85% NaC1 (i.p.). Twenty-four hours after the last injection. the animals were decapitated and liver microsomal fractions were isolated. The concentration of proteins and the content of cytochromes b s and P450 were measured. The rates of NADPH and NADH oxidation, aminopyrine demethylation, and aniline p-hydroxylation and activities of NADPH-cytochrome P450 and NADH-cytochrome b 5 oxidoreductases, uridine 5'-diphosphoglucuronyl transferase (UDP-glucuronosyltransferase), glutathione S-transferase, and uridine-5'-diphosphoglucose dehydrogenase (UDP-glucose dehydrogenase) were estimated by the method described elsewhere [3]. The urinary excretion of glucuronic acid [14] and activity of alanine transaminase (ALT) in the serum [5] were estimated. RESULTS