Inhibition of 3,5,2′,4′-Tetrahydroxychalcone on Production of Uric Acid in Hypoxanthine-Induced Hyperuricemic Mice

Abstract

The mechanism of 3,5,2′,4′-tetrahydroxychalcone on lowing urate level is still unknown. Here we investigated the effects of 3,5,2′,4′-tetrahydroxychalcone on urate levels, xanthine oxidase/xanthine dehydrogenase (XOD/XDH) activities in hypoxanthine-induced hyperuricemic mice, as well as the effects of 3,5,2′,4′-tetrahydroxychalcone on the mRNA expression levels and content of phosphoribosyl pyrophosphate synthetase (PRPS), phosphoribosyl pyrophosphate amidotransferase (PRPPAT) and hypoxanthine-guanine phosphoribosyl transferase (HGPRT). Our results demonstrated that 3,5,2′,4′-tetrahydroxychalcone (1.0, 2.0, and 4.0 mg/kg) reduced the uric acid levels in serum of the hyperuricemic mice in dose-and time-dependent manners. The activities of XOD/XDH in serum and liver were also significantly inhibited by 3,5,2′,4′-tetrahydroxychalcone; In addition, 3,5,2′,4′-tetrahydroxychalcone decreased the mRNA expression of HGPRT in brain and content of PRPS and PRPPAT in liver. These findings demonstrated that 3,5,2′,4′-tetrahydroxychalcone suppresses uric acid production by affecting the critical enzymes, XOD/XDH, PRPS, PRPPAT and HGPRT in purine nucleotide metabolism.Key words 3,5,2′,4′-tetrahydroxychalcone; purine metabolism enzyme; hyperuricemia Gout and hyperuricemia are metabolic disorders associated with abnormal amounts of uric acid in the body. The overproduction of uric acid is one of the major factors in most patients with gout. Maintaining uric acid level <6 mg/dL is important for prevention of gout. Many enzymes participated in purine metabolic pathway, such as xanthine oxidase/xanthine dehydrogenase (XOD/XDH), hypoxanthine-guanine phosphoribosyl transferase (HGPRT), phosphoribosyl pyrophosphate synthetase (PRPS), and phosphoribosyl pyrophosphate aminotransferase (PRPPAT).1) The dysfunction of these enzymes increases the production of uric acid, resulting in hyperuricemia.2) Particularly, the XOD has been recognized as one of the promising targets for the treatment of hyperuricemia. Allopurinol, a potent XOD inhibitor with a purine backbone, has been used clinically for more than 50 years.3,4) However, allopurinol induces serious side effects such as renal failure, impaired hepatic function and allergic reactions, 5) limiting its clinical application. Recently, a new non-purine XOD inhibitor, Febuxostat, has been approved for management of gout in the European Union and USA. 6) But a few side effects of febuxostat have been reported, 7) such as liver function abnormalities, nausea, arthralgias, and rash. Therefore, novel alternatives to allopurinol with potent XOD inhibitory activity and less side effects are in great demand.3,5,2′,4′-Tetrahydroxychalcone is one of chalcones (Fig. 1). It has been reported to possess various pharmacological activities, such as antitumor, 8) free radical scavenging, 9) antibiosis, 10) antiulcer 11) and spasmolysis. 12) Currently, there are few reports about their inhibitory effects against the XOD activity. In a previous study, we reported that 3,5,2′,4′-tetrahydroxychalcone had an i...

From Xanthine Oxidase Inhibition to In Vivo Hypouricemic Effect: An Integrated Overview of In Vitro and In Vivo Studies with Focus on Natural Molecules and Analogues

“…e chalcone scaffold, found in many naturally occurring compounds, have a wide range of bioactive properties and have also been prepared by synthesis [48,49]. As an example, Li and co-workers [50][51][52] prepared several chalcones and evaluated their XO inhibitory activity. Of these, 3,5,2′,4′-tetrahydroxychalcone ( Figure 15 an interesting XO inhibition in a competitive manner, and IC 50 and K i values of 22.5 and 17.4 μM, respectively, were determined [52].…”

“…e best effect occurred with doses between 2 and 4 mg/kg [50][51][52]. Studies performed by the authors suggested that this chalcone act by a dual mechanism [50].…”

“…e best effect occurred with doses between 2 and 4 mg/kg [50][51][52]. Studies performed by the authors suggested that this chalcone act by a dual mechanism [50]. In fact, this in vivo hypouricemic action can be associated not only with the inhibition of key enzymes (XO, PRPS, PRPPAT, and HGPRT) in the purine metabolism but also with an enhancement in UA excretion by inhibiting the expression of GLUT9 in the kidney [50,51].…”

“…Studies performed by the authors suggested that this chalcone act by a dual mechanism [50]. In fact, this in vivo hypouricemic action can be associated not only with the inhibition of key enzymes (XO, PRPS, PRPPAT, and HGPRT) in the purine metabolism but also with an enhancement in UA excretion by inhibiting the expression of GLUT9 in the kidney [50,51]. Finally, an acute toxicity study in mice showed that 3,5,2′,4′-tetrahydroxychalcone was safe at a dose up to 5 g/kg, making it suitable for future studies [52].…”

The Efficacy and Mechanism of Chinese Herbal Medicines in Lowering Serum Uric Acid Levels: A Systematic Review

“…Among these key enzymes, XO is the most commonly studied enzyme. 3,5,2′,4′-tetrahydroxychalcone significantly inhibits the activities of XO in liver, and the decreased content of PRPP in liver will suppresse the UA production (Niu et al, 2018). In our review, nearly half of the studies (83/186, 45%) confirm that herbs regulate XO synthesis and activity.…”