Abstract
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.
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Abbreviations
- AST:
-
aspartate aminotransferase
- ALT:
-
alanine aminotransferase
- BDL:
-
bile duct-ligated
- MOPS:
-
3-(N-morpholino)propanesulfonic acid
- TBARS:
-
thiobarbituric acid reacting substances
- XHD:
-
xanthine dehydrogenase
- XO:
-
xanthine oxidase
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Supported in part by National Institutes of Health Grants DK38446 and IP30DK34914 and by the Abbey Bennett Liver Research Fund.
Presented in part at the Annual Meeting of the American Association for the Study of Liver Diseases, November, 1995, in Chicago, IL, and published in abstract form (Hepatology 1995;22:317A).
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Sokol, R., Devereaux, M. & Khandwala, R. Effect of Oxypurinol, a Xanthine Oxidase Inhibitor, on Hepatic Injury in the Bile Duct-Ligated Rat. Pediatr Res 44, 397–401 (1998). https://doi.org/10.1203/00006450-199809000-00022
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DOI: https://doi.org/10.1203/00006450-199809000-00022
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