Tissue protective effect of xanthine oxidase inhibitor, polymer conjugate of (styrene-maleic acid copolymer) and (4-amino-6-hydroxypyrazolo[3,4-d]pyrimidine), on hepatic ischemia-reperfusion injury.

The detrimental role of superoxide anion (O(2)(-)) has been well documented in the pathogenesis of ischemia-reperfusion (I/R) injury. Our and other studies suggested that one critical source of O(2)(-) generation may be xanthine oxidase (XO). We thus hypothesized that I/R injury could be protected by inhibiting XO activity, which would reduce the amount of O(2)(-) and hence reduce pathogenic consequences. Among various XO inhibitors, we previously found 4-amino-6-hydroxypyrazolo[3,4-d]pyrimidine (AHPP) exhibited potent XO inhibitory activity. Here, we report that the covalent conjugate of AHPP with amphipathic styrene-maleic acid copolymer (SMA-AHPP) showed protective effect against I/R-induced injury in a rat hepatic I/R model. Liver ischemia was induced by occluding both the portal vein and the hepatic artery for 30 min, and followed by reperfusion. SMA-AHPP was administered via the tail vein two hours before ischemia was initiated. A remarkable increase of liver enzymes in plasma (aspartate aminotransferase, AST; alanine aminotransferase, ALT and lactate dehydrogenase, LDH) was detected three hours after reperfusion, whereas prior injection of SMA-AHPP greatly suppressed this increase of AST, ALT and LDH. Moreover, induction of inflammatory cytokines, i.e. tumor necrosis factor-alpha (TNF-alpha), interleukin-12 (IL-12) and monocyte chemotactic protein-1 (MCP-1) by I/R were significantly inhibited by SMA-AHPP treatment. Accordingly, cytotoxic effect or apoptosis in the liver caused by I/R was clearly reduced by SMA-AHPP pretreatment. Furthermore, thiobarbituric acid-reactive substance assay showed a significant decrease of lipid peroxidation in rat liver after the administration of SMA-AHPP, which is parallel with the decreased XO activity after SMA-AHPP treatment, indicating the involvement of reactive oxygen species generated by XO. In addition, SMA-AHPP was found to bind to albumin, thus to exhibit prolonged in vivo (plasma) half-life. These results suggest that SMA-AHPP exerted a potent cytoprotective effect against I/R injury in rat liver, by inhibiting XO activity and the subsequent generation of O(2)(-).
AuthorsJun Fang, Takahiro Seki, Haibo Qin, Gahininath Y Bharate, Arun K Iyer, Hiroshi Maeda
JournalExperimental biology and medicine (Maywood, N.J.) (Exp Biol Med (Maywood)) Vol. 235 Issue 4 Pg. 487-96 (Apr 2010) ISSN: 1535-3699 [Electronic] England
PMID20407081 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • 4-amino-6-hydroxypyrazolo(3,4-d)pyrimidine
  • Albumins
  • Cytokines
  • Enzyme Inhibitors
  • Maleates
  • Polystyrenes
  • Thiobarbituric Acid Reactive Substances
  • Superoxides
  • styrene-maleic acid polymer
  • Heme Oxygenase-1
  • Xanthine Oxidase
  • Oxypurinol
  • Albumins (metabolism)
  • Animals
  • Apoptosis (drug effects)
  • Cytokines (blood)
  • Enzyme Inhibitors (chemistry, pharmacology)
  • Heme Oxygenase-1 (metabolism)
  • Liver (blood supply, drug effects, metabolism, pathology)
  • Male
  • Maleates (chemistry, pharmacology)
  • Molecular Weight
  • Oxypurinol (analogs & derivatives, chemistry, pharmacology)
  • Polystyrenes (chemistry, pharmacology)
  • Rats
  • Rats, Wistar
  • Reperfusion Injury (metabolism, pathology, prevention & control)
  • Superoxides (metabolism)
  • Thiobarbituric Acid Reactive Substances (metabolism)
  • Tissue Distribution
  • Xanthine Oxidase (antagonists & inhibitors, metabolism)

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