Hypouricemic effect of 2,4-dihydroxybenzoic acid methyl ester in hyperuricemic mice through inhibiting XOD and down-regulating URAT1

In this paper, we reported the hypouricemic effect of 2,4-dihydroxybenzoic acid methyl ester (DAE), a component of Ganoderma applanatum, in hyperuricemic mice through inhibiting XOD and down-regulating URAT1. Computationally, DAE showed a high similarity to allopurinol and depicted a high affinity in docking to XOD. In vitro, DAE exhibited an inhibitory effect against XOD. Importantly, DAE demonstrated a remarkable hypouricemic effect, decreasing serum uric acids (SUAs) of hyperuricemic mice (407 +/- 31 mu mol/L) to 195 +/- 23, 145 +/- 33 and 134 +/- 16 mu mol/L (P < 0.01) at the doses of 20, 40, and 80 mg/kg with a dose-dependent manner and showing efficacies at 54-68 %, which were close to the efficacies of allopurinol (61 %) and benzbromarone (57 %). DAE depicted higher and negatively dose-independent urinary uric acids in comparison with that of the hyperuricemic control, implying DAE exerted an uricosuric effect and also a reduction effect on uric acid production. Unlike toxic allopurinol and benzbromarone, no general toxicity on body weights and no negative influence on liver, kidney, spleen and thymus were observed for DAE. Mechanistically, DAE inhibited XOD activities in vivo. Moreover, DAE up-regulated OAT1 and down-regulated GLUT9, URAT1 and CNT2. Overall, DAE may present a hypouricemic effect through inhibiting XOD and up-regulating OAT1 and down-regulating GLUT9, URAT1 and CNT2. This work provided novel insights into the hypouricemic effect of DAE and G. applanatum.

Automated summary

This paper reports the hypouricemic effect of 2,4-dihydroxybenzoic acid methyl ester (DAE) from Ganoderma applanatum on hyperuricemic mice. DAE inhibits XOD and down-regulates URAT1, showing high similarity and affinity to allopurinol. In vitro, DAE exhibits inhibitory effect against XOD. Importantly, DAE demonstrates remarkable hypouricemic effect on hyperuricemic mice, with no toxicity observed. Mechanistically, DAE inhibits XOD activities and up-regulates OAT1 while down-regulating GLUT9, URAT1, and CNT2.