Enhanced activity of the free radical producing enzyme xanthine oxidase in hypoxic rat liver. Regulation and pathophysiologic significance.
It has been widely proposed that conversion of xanthine dehydrogenase (XDH) to its free radical-producing form, xanthine oxidase (XOD), underlies ischemic/reperfusion injury, although the relationship of this conversion to hypoxia and its physiologic control have not been defined. This study details the time course and control of this enzymatic interconversion. In a functionally intact, isolated perfused rat liver model, mean % XOD activity increased as a function of both the duration (25 to 45% in 3 h) and degree (r = 0.97) of hypoxia. This process was markedly accelerated in ischemic liver by an overnight fast (45 vs. 30% at 2 h), and by imposing a short period of in vivo ischemia (cardiopulmonary arrest 72%). Moreover, only under these conditions was there a significant rise in the XOD activity due to the conformationally altered XDH molecule (XODc, 18%), as well as concomitant morphologic injury. Neither circulating white blood cells nor thrombosis appeared to contribute to the effects of in vivo ischemia on enzyme conversion. Thus, it is apparent that conversion to the free radical-producing state, with high levels of XOD activity and concurrent cellular injury, can be achieved during a relatively short period of hypoxia under certain well-defined physiologic conditions, in a time course consistent with its purported role in modulating reperfusion injury. These data also suggest that the premorbid condition of organ donors (e.g., nutritional status and relative state of hypoxia) is important in achieving optimal organ preservation.
Brass
C A
CA
Gastroenterology Division, Brigham and Women's Hospital, Boston, Massachusetts.
Narciso
J
J
Gollan
J L
JL
D000818:Animals; D005609:Free Radicals; D066298:In Vitro Techniques; D008099:Liver / Q000201:enzymology* / Q000502:physiology / Q000503:physiopathology; D009503:Neutropenia / Q000378:metabolism; D010101:Oxygen Consumption; D051381:Rats; D011919:Rats, Inbred Strains; D015427:Reperfusion Injury / Q000378:metabolism; D014968:Xanthine Dehydrogenase / Q000378:metabolism; D014969:Xanthine Oxidase / Q000378:metabolism*
D005609:Free Radicals; D014968:Xanthine Dehydrogenase; D014969:Xanthine Oxidase