Lonicera hypoglauca Inhibits Xanthine Oxidase and Reduces Serum Uric Acid in Mice

Abstract

Xanthine oxidase (XOD) catalyzes the oxidation of hypoxanthine to xanthine and then to uric acid, and is a key enzyme in the pathogenesis of hyperuricemia. The ability of extracts of Lonicera hypoglauca (Caprifoliaceae) to inhibit XOD was investigated in this study. An ethanol extract (LH-crude) of the leaves of L. hypoglauca and its derived EtOAc soluble sub-fractions (LH‐EA) significantly inhibited XOD activity, with IC₅₀ values for LH-crude and LH‐EA of 48.8 and 35.2 µg/mL. Moreover, LH‐EA reduced serum urate levels in vivo in a potassium oxonate-induced hyperuricemic mouse model, by 70.1 % and 93.7 % of the hyperuricemic untreated group at doses of 300 and 500 mg/kg of LH‐EA, respectively. Finally, we used bioactivity-guided fractionation to isolate a new bisflavonoid, loniceraflavone, which showed significant inhibition of XOD (IC₅₀ = 0.85 µg/mL). These results suggest that L. hypoglauca and its extracts may have a considerable potential for development as an anti-hyperuricemia agent for clinical application.

Key words

Lonicera hypoglauca - Caprifoliaceae - hyperuricemia - xanthine oxidase inhibitor - loniceraflavone

References

• 1 Efferth T, Li P CH, Konkimalla V SB, Kaina B. From traditional Chinese medicine to rational cancer therapy.  Trends Mol Med. 2007;  13 353-361
• 2 Peng Y, Liu F, Ye J. Determination of phenolic acids and flavones in Lonicera japonica Thunb. by capillary electrophoresis with electrochemical detection.  Electroanalysis. 2005;  17 356-362
• 3 Kumar N, Singh B, Bhandari P, Gupta A P, Uniyal S K, Kaul V K. Biflavonoids from Lonicera japonica.  Phytochemistry. 2005;  66 2740-2744
• 4 Lu F Y, Ou C H, Chen Y C, Chi Y S, Lu K C. Tree of Taiwan I. Taichung; National Chung-Hsing University Press 2000
• 5 Kong L D, Cai Y, Huang W W, Cheng C HH, Tan R X. Inhibition of xanthine oxidase by some Chinese medicinal plants used to treat gout.  J Ethnopharmacol. 2000;  73 199-207
• 6 Wang S Y, Yang C W, Liao J W, Zhen W W, Chu F H, Chang S T. Essential oil from leaves of Cinnamomum osmophloeum acts as a xanthine oxidase inhibitor and reduces the serum uric acid levels in oxonate-induced mice.  Phytomedicine. 2008;  15 940-945
• 7 Zimmermann M. Ethical guidelines for investigations of experimental pain in conscious animals.  Pain. 1983;  16 109-110
• 8 Stavric B, Clayman S, Grodd R EA, Hebert D. Some in vivo effects in the rat induced by chlorprothixene and potassium oxonate.  Pharmacol Res Commun. 1975;  7 117-124
• 9 Zhao X, Zhu J X, Mo S F, Pan Y, Kong L D. Effect of Cassia oils on serum and hepatic uric acid levels in oxonate-induced mice and xanthine dehydrogenase and xanthine oxidase activities in mouse liver.  J Ethnopharmacol. 2006;  103 357-365
• 10 Unno T, Sugimoto A, Kakuda T. Xanthine oxidase inhibitors from the leaves of Lagerstroemia speciosa (L.) Pers.  J Ethnopharmacol. 2004;  93 391-395
• 11 Kong L, Zhou J, Wen Y, Li J, Cheng C HK. Aesculin possesses potent hypouricemic action in rodents but is devoid of xanthine oxidase/dehydrogenase inhibitory activity.  Planta Med. 2002;  68 175-178
• 12 Shimoto T, Ashizawa N, Matzumoto K, Nakazawa T, Nagata O. Simultaneous treatment with citrate prevents nephropathy induced by FYX‐051, a xanthine oxidoreductase inhibitor, in rats.  Toxicol Sci. 2005;  87 267-276
• 13 Ramallo I A, Zacchino S A, Furlan R LE. A rapid TLC autographic method for the detection of xanthine oxidase inhibitors and superoxide scavengers.  Phytochem Anal. 2006;  17 15-19
• 14 Carroll J J, Roberta D HC, Badson A L. A simplified alkaline phosphotungstate assay for uric acid in serum.  Clin Chem. 1971;  17 158-160
• 15 Field M, Lewis C G, Lure M D. Allopurinol, an inhibitor of xanthine oxidase, reduces uric acid levels and modifies the signs associated with copper deficiency in rats fed fructose.  Free Radic Biol Med. 1996;  20 595-600