No abstract

Thiamine (10(-4)-10(-6)M) inhibits lipid peroxidation in rat liver microsomes and free radical oxidation of oleic acid in vitro. Thiamine interacts with free radicals and hydroperoxides and is oxidized to thiochrome and thiamine disulfide. The antioxidant effect of thiamine is probably related to successive transfer of 2H(+)from the NH(2)group of the pyrimidine ring and H(+)from the thiazole ring (after its opening) to reactive substrates.

Intoxication with deoxycholic acid is accompanied by destruction of hepatocyte plasma membrane (increased serum alanine aminotransferase activity) and inhibition of monooxygenase, glucuronidase and glutathione systems of rat liver. Heptral and cordiamine (mitethamide) had no effect on membrane integrity, while a-tocopherol and ursofalk (ursodeoxycholic acid) protected membranes. Ursofalk and cordiamine are superior a ~-tocopherol and heptral by their ability to activity of monooxygenase, glucuronidase, and glutathione conjugating systems in the liver.

On the eighth day after ligation of the common bile duct in rats a significant increase in the serum content of total lipids, cholesterol bilirubin and ALT, alkaline phosphatase, and gamma-glutamyltransferase was observed. In the microsomal fraction there was a marked decrease in the content and activity of microsomal monooxygenases. Introperitoneal injection of berberine (10 mg/kg) for 6 days caused a partial normalization of permeability of hepatocytes plasma membranes and activity of microsomal flavin-containing monooxygenases. It is suggested that berberine is a substrate and inducer of flavin-containing monooxygenases. Membrane-stabilizing effect of berberine is probably realized at the level of inhibition of prooxidant status of liver cells.

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