Eurycomanol alleviates hyperuricemia by promoting uric acid excretion and reducing purine synthesis

An elevated level of blood uric acid (UA) leads to serious damages to human health. In clinic, xanthine oxidase inhibitor is commonly used to reduce uric acid production. However, UA excretion promotion drug is rare. Our previous study demonstrated that the 70% ethanolic extract of stem of Eurycoma longifolia could effectively increase UA excretion and decrease blood level of UA in hyperuricemia animal model. In this paper, we tried to find active substance on UA regulation from E. longifolia.The constituents of stem from E. longifolia were isolated and analyzed by chemical and spectral methods. Ultra Performance Liquid Chromatography was applied to measure the concentrations of UA in serum and urine. H&E staining was used to characterize renal histopathological changes. The protein and mRNA expressions of UA transporters were measured by western blot and quantitative real-time PCR analysis.Ten kinds of quassinoids were isolated from stem of E. longifolia, and the structures were identified. Pharmacological research revealed the major component, eurycomanol (5-20 mg/kg, p.o.) significantly decreased serum UA level and increased 24 h clearance of uric acid in potassium oxonate and adenine induced hyperuricemic mice. Eurycomanol ameliorated UA induced kidney histological injury, inhibited hepatic purine synthesis through decreasing phosphoribosyl pyrophosphate synthetase, promoted UA excretion by modulation of renal and intestinal urate transporters, such as GLUT9, ABCG2, OAT1, and NPT1.The results showed eurycomanol from E. longifolia can promote UA excretion through kidney and intestine, decrease hepatic purine synthesis and further keep UA homeostasis, suggesting that eurycomanol has the potential to be developed into a novel drug for the treatment of under-excretion type hyperuricemia.