Significance of xanthine oxidase in the production of intracellular oxygen radicals in an in-vitro hypoxia-reoxygenation model.
OBJECTIVE
The peroxidation of membranous phospholipids induced by ischemia reperfusion was inhibited in Cu/Zn superoxide dismutase (SOD) overexpressing mice, suggesting a detrimental role for intracellular reactive oxygen species (ROS) in reoxygenated cell injury. To ascertain the in-vitro relevance of this hypothesis, the present study examined the participation of intracellular ROS in reoxygenation injury.


METHODS
This examination was done in two experimental models: Cu/Zn-SOD transgenic (Tg) mice that underwent hypoxia-reoxygenation in vitro and normal mice pretreated with a specific inhibitor of xanthine oxidase, BOF-4272, followed by in vitro hypoxia-reoxygenation.


RESULTS
The release of aspartate aminotransferase (AST) and the peroxidation of phospholipids were both ameliorated in hepatocytes from the Tg mice compared with findings in hepatocytes from normal mice. Similar findings were seen in the BOF-4272-pretreated cells, in which there was a decrease in AST and phospholipid peroxides.


CONCLUSIONS
These results support the pivotal role of intracellular ROS generated by xanthine oxidase in reoxygenated cell injury, and suggest the viability of using an intracellular antioxidative therapy for reperfusion injury of the liver.
Department of Surgery, Division of Gastroenterological Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan.
Tetsuya
T
Kakita
Masanori
M
Suzuki
Heigo
H
Takeuchi
Michiaki
M
Unno
Seiki
S
Matsuno
D000255:Adenosine Triphosphate / Q000032:analysis; D000818:Animals; D024443:Aspartate Aminotransferase, Cytoplasmic / Q000032:analysis; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D066298:In Vitro Techniques; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D010713:Phosphatidylcholines / Q000032:analysis; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015427:Reperfusion Injury / Q000378:metabolism* / Q000517:prevention & control / Q000628:therapy; D013482:Superoxide Dismutase / Q000235:genetics; D014227:Triazines / Q000494:pharmacology; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors / Q000502:physiology*
D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D010713:Phosphatidylcholines; D017382:Reactive Oxygen Species; D014227:Triazines; C057590:phosphatidylcholine hydroperoxide; C072977:BOF 4272; D000255:Adenosine Triphosphate; D013482:Superoxide Dismutase; D014969:Xanthine Oxidase; D024443:Aspartate Aminotransferase, Cytoplasmic