Phytochemicals from Acacia confusa heartwood extracts reduce serum uric acid levels in oxonate-induced mice: their potential use as xanthine oxidase inhibitors.
In this study, the antihyperuricemic effect of Acacia confusa heartwood extracts and their phytochemicals on potassium oxonate (PO)-induced acute hyperuricemia was investigated for the first time. All treatments at the same dosage (100 mmol/kg) were administered to the abdominal cavity of PO-induced hyperuricemic mice, and serum uric acid level was measured at 3 h after administration. In experimental mice, serum uric acid level was significantly suppressed by the administration of A. confusa heartwood extracts and their major phytochemicals, (-)-2,3-cis-3,4-cis-3,3',4,4',7,8-hexahydroxyflavan, (-)-2,3-cis-3,4-cis-4'-methoxy-3,3',4,7,8-pentahydroxyflavan, melanoxetin, transilitin, and okanin, relative to the PO group. The direct inhibitory effect of these five compounds on xanthine oxidase (XOD) activity was examined using isothermal titration calorimetry (ITC). Among them, melanoxetin showed a more remarkable inhibitory effect on XOD activity than allopurinol, a clinical drug used for XOD inhibitor. To further understand the stereochemistry between XOD and melanoxetin (or allopurinol), structure-based molecular modeling was performed. Melanoxetin undergoes extended interactions in the hydrophobic region via the 3',4'-dihydroxyphenyl moiety, thus accounting for its higher binding affinity to XOD than allopurinol. These results indicate that A. confusa heartwood extracts and their major phytochemicals exhibit strong XOD inhibitory effects, which reduce serum uric acid levels while inhibiting uric acid generation in purine metabolism.
Tung
Yu-Tang
YT
School of Forestry and Resource Conservation, National Taiwan University, Taipei 106, Taiwan.
Hsu
Chih-An
CA
Chen
Chien-Shu
CS
Yang
Suh-Ching
SC
Huang
Chi-Chang
CC
Chang
Shang-Tzen
ST
D000045:Acacia / Q000737:chemistry*; D000818:Animals; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000627:therapeutic use* / Q000633:toxicity; D005419:Flavonoids / Q000737:chemistry / Q000302:isolation & purification / Q000627:therapeutic use*; D033461:Hyperuricemia / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010094:Oxonic Acid / Q000633:toxicity; D010936:Plant Extracts / Q000737:chemistry* / Q000627:therapeutic use; D014503:Urate Oxidase / Q000037:antagonists & inhibitors; D014527:Uric Acid / Q000097:blood; D014934:Wood / Q000737:chemistry; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors* / Q000737:chemistry
D004791:Enzyme Inhibitors; D005419:Flavonoids; D010936:Plant Extracts; D014527:Uric Acid; C489337:potassium oxonate; D010094:Oxonic Acid; D014969:Xanthine Oxidase; D014503:Urate Oxidase