Role of purines and xanthine oxidase in reperfusion injury in perfused rat liver.
The purpose of this study was to evaluate the possible involvement of xanthine and xanthine oxidase in reperfusion injury in a low-flow, reflow model of liver perfusion. Livers were perfused at flow rates around 25% of normal for 90 min and then at normal flow rates (4 ml/g/min) for 30 min. When flow was restored to normal, malondialdehyde and lactic dehydrogenase (LDH) were released into the effluent perfusate. Malondialdehyde production rapidly reached values of 300 nmol/g/hr whereas LDH increased from basal levels of 100 to 600 U/l upon reperfusion. Trypan blue was taken up exclusively in cells in pericentral regions of the liver lobule under these conditions. Xanthine and hypoxanthine in the effluent perfusate increased steadily during the low-flow period reaching values around 5 and 10 microM, respectively, and decreased rapidly after the flow was restored to normal. Perfusion with nitrogen-saturated buffer for 3 min before restoration of normal flow rates or infusion of the radical scavenger catechin (400 microM) reduced cell damage by about 50%. Infusion of allopurinol (2-6 mM), an inhibitor of xanthine oxidase, prevented reperfusion injury in a dose-dependent manner. Taken together, these data indicate that a reperfusion injury occurs in liver upon reintroduction of oxygen which is initiated by oxidation of xanthine and hypoxanthine via xanthine oxidase and ultimately leads to production of lipid peroxides. Surprisingly, infusion of xanthine (4 mM), substrate for xanthine oxidase, reduced hepatocellular injury on reperfusion. LDH release was decreased from values around 700 to less than 200 U/l and trypan blue uptake in pericentral region was prevented totally by xanthine.(ABSTRACT TRUNCATED AT 250 WORDS)
Zhong
Z
Z
Laboratory of Hepatobiology and Toxicology, University of North Carolina, Chapel Hill.
Lemasters
J J
JJ
Thurman
R G
RG
D000818:Animals; D005260:Female; D019271:Hypoxanthine; D007042:Hypoxanthines / Q000502:physiology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008102:Liver Circulation; D008315:Malondialdehyde / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D015427:Reperfusion Injury / Q000209:etiology*; D013481:Superoxides / Q000378:metabolism; D014527:Uric Acid / Q000378:metabolism / Q000494:pharmacology; D019820:Xanthine; D014969:Xanthine Oxidase / Q000502:physiology*; D014970:Xanthines / Q000502:physiology*
D007042:Hypoxanthines; D014970:Xanthines; D013481:Superoxides; D019820:Xanthine; D014527:Uric Acid; D019271:Hypoxanthine; D008315:Malondialdehyde; D007770:L-Lactate Dehydrogenase; D014969:Xanthine Oxidase