oxypurinol and Liver-Diseases

Oxidant stress has been implicated as playing a role in the pathogenesis of cholestatic liver injury. The objective of this study was to determine whether the xanthine oxidase/xanthine dehydrogenase enzyme system was involved in this oxidant stress. Adult Sprague-Dawley rats were treated with the xanthine oxidase inhibitor, oxypurinol, and randomized to bile duct ligation or sham surgery; vehicle-treated, sham-operated rats served as controls. After 5 d of bile duct ligation, serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and total and direct bilirubin concentrations were significantly elevated, and increased lipid peroxidation of hepatic mitochondria and microsomes was present. Treatment with oxypurinol reduced the aspartate aminotransferase, alanine aminotransferase, and bilirubin values by 26-47% but did not alter the increased lipid peroxidation of mitochondria and microsomes. Serum vitamin E:total lipids ratio was also reduced in both bile duct-ligated groups, consistent with oxidant injury. These data show that inhibition of xanthine oxidase reduces biochemical evidence of hepatocellular injury during bile duct ligation without affecting oxidant damage to intracellular hepatocyte organelles. Thus, in this model a component of cholestatic injury appears to have been caused by oxidant stress from a source outside of the hepatocyte.

Topics: Animals; Bile Ducts; Enzyme Inhibitors; Liver; Liver Diseases; Male; Oxidative Stress; Oxypurinol; Rats; Rats, Sprague-Dawley; Xanthine Oxidase

Reoxygenation injury that occurs when blood circulation is restored to previously ischemic tissues is currently discussed as a pathophysiological entity distinct from the primary anoxic injury that develops during ischemia per se. To test the hypothesis that reoxygenation injury in hepatocytes is caused by a postischemic burst of reactive oxygen species (ROS), including superoxide radicals, O2-., and hydrogen peroxide, H2O2, we performed a cytochemical study exploiting the peroxidase activity within peroxisomes as a sensitive ultrastructural detector of intracellular H2O2 generation. The osmiophilic polymer formed when tissue peroxidase is incubated with 3,3'-diaminobenzidine (DAB) and H2O2 was used as a marker for endogenous H2O2 in rat liver slices in short-term organ culture subjected to a cycle of 60-min ischemic anoxia and 30-min reoxygenation in the presence of DAB without exogenous H2O2. Peroxisomal reaction product was quantitatively evaluated in transmission electron micrographs of systematically sampled hepatocytes. Mean densities of positive peroxisomes per 1,000 micron2 (+/- SE) in liver slices subjected to various treatments were as follows: continuous anoxia (negative control) 0 +/- 0; normoxia + exogenous H2O2 (positive control) 45 +/- 12; normoxia only 26 +/- 2; ischemia-reoxygenation 13 +/- 6; ischemia-reoxygenation + xanthine oxidase inhibitor, oxypurinol 5 +/- 3; ischemia-reoxygenation + peroxidase inhibitor, aminotriazole 7 +/- 3. Endogenous H2O2 can be detected in hepatocytes by electron microscopic cytochemistry and may in part derive from xanthine oxidase, but it is not substantially increased in the postischemic state. We conclude that hepatocytes do not exhibit a postischemic burst of reactive oxygen species that could cause reoxygenation injury.

Topics: Amitrole; Animals; Histocytochemistry; Hydrogen Peroxide; Ischemia; Liver; Liver Diseases; Male; Microbodies; Microscopy, Electron; Oxygen; Oxypurinol; Rats; Rats, Inbred Strains; Reperfusion Injury

Liver function can be assessed by administering an exogenous substance to quantify changes in hepatic blood flow, uptake, biotransformation, and excretion. Characterization of drug half-life, clearance, and product formation rates are possible methods for measuring hepatic efficiency. Allopurinol and caffeine have been used to measure metabolite formation followed by renal elimination of both parent substance and metabolite. Sorbitol, a substance with high intrinsic clearance, can reflect liver blood flow, while trimethadione, a low-extraction drug, has been used to measure liver enzyme capacity. Metabolites from lidocaine, methacetin, and aminopyrine have been measured in serum, urine, and breath tests. Salivary clearance measurements of caffeine and antipyrine are reported as suitable for routine use. Genetic diversity of isoenzymes and the many metabolic processes used by hepatocytes make it extremely difficult to quantify functional changes with one substance. Combinations of model substrates have been suggested to assess the many hepatic processes.

Topics: Acetamides; Adult; Allopurinol; Aminopyrine; Caffeine; Half-Life; Humans; Indocyanine Green; Lidocaine; Liver; Liver Circulation; Liver Diseases; Liver Function Tests; Metabolic Clearance Rate; Middle Aged; Oxypurinol; Pyrimidines; Sorbitol

A newly developed liver function test was performed on 18 apparently healthy individuals and 29 patients with liver disease. After intravenous injection of a low dose allopurinol (17.1 mumol/kg body mass), blood specimens were collected during 1 h. Plasma analyses of allopurinol and its metabolite oxipurinol were performed and the data were processed by means of a computer-based biodynamic model. This modelling approach makes it possible to estimate parameters, containing information about liver perfusion, hepatocyte membrane transport and hepatocyte cell mass. One parameter (kA31) showed complete discrimination between the reference sample group of healthy individuals and patients with severe liver dysfunction. In a reference sample group of patients with slightly to moderately reduced liver function, only a few patients (5/20) had a kA31 value over the decision limit. In this respect, the allopurinol loading test is superior to the conventional intravenous galactose tolerance test.

Topics: Adolescent; Adult; Aged; Allopurinol; Evaluation Studies as Topic; Female; Galactosemias; Humans; Injections, Intravenous; Liver Diseases; Liver Function Tests; Male; Middle Aged; Oxypurinol; Time Factors

Topics: Allopurinol; Humans; Injections, Intravenous; Kinetics; Liver Diseases; Liver Function Tests; Models, Biological; Oxypurinol