Morin (3,5,7,2′,4′-Pentahydroxyflavone) Exhibits Potent Inhibitory Actions on Urate Transport by the Human Urate Anion Transporter (hURAT1) Expressed in Human Embryonic Kidney Cells

Abstract

ABSTRACT:In allopurinol-allergic patients, uricosuric agents are often used in the treatment of hyperuricemia. The existing uricosuric agents are not without problems and the availability of better and safer alternatives is highly desirable. Our previous study (J Pharmacol Exp Ther (2006) 316:169-175) has demonstrated that morin (3,5,7,2,4-pentahydroxyflavone), which occurs in the twigs of Morus alba L. documented in traditional Chinese medicinal literature for treatment of conditions akin to gout, is a potent inhibitor of urate uptake in rat renal brush-border membrane vesicles. It is also effective in lowering uric acid level in a hyperuricemic rat model in vivo. Whether morin is an equally effective uricosuric agent in human requires verification. The human urate anion transporter (hURAT1) has recently been cloned and identified to be the organic anion transporter that mediates renal urate reabsorption in the human kidney. In the present investigation, human embryonic kidney cells were transfected with hURAT1 and the expression was validated by reverse transcription-polymerase chain reaction and subcellular distribution of the exogenously introduced transporter by confocal microscopy. The inhibitory actions of morin on human renal urate reabsorption were demonstrated using this system. The IC 50 value of the inhibition by morin was determined to be 2.0 M, compared with 50 M for probenecid, 100 M for sulfinpyrazone, and 0.3 M for benzbromarone. Kinetic analysis of the uptake inhibition by morin indicates that this compound is a competitive inhibitor of urate uptake on the human urate transporter with a K i value of 5.74 M.

Biodistribution, hypouricemic efficacy and therapeutic mechanism of morin phospholipid complex loaded self-nanoemulsifying drug delivery systems in an experimental hyperuricemic model in rats

“…demonstrated that morin inhibited XDH/XO activity in vitro with low micromolar potency . Morin was also shown to inhibit the human URAT1 expressed in human embryonic kidney cells . Moreover, Wang et al .…”

“…Recently, some of the renal organic anion transporters were identified in the brush‐border membrane of the proximal tubule in rat kidney and played key roles in mediating renal uric acid excretion, such as GLUT9 (encoded by SLC2A9), URAT1 (encoded by SLC22A12) and OAT1 (encoded by SLC22A6). Mutations in GLUT9 deficiency cause urate reabsorption reduction, resulting in the increased serum uric acid levels and FEUA .…”

Modulation of the activity of ABC transporters (P-glycoprotein, MRP2, BCRP) by flavonoids and drug response

“…Although the majority of flavonoid interactions mediated by ABC transporters seem to be smaller than the CYP‐mediated effects, more specific substrates are needed to understand the results and to establish therapeutic strategies. In combination with metabolism enzymes, several transporters also interact with flavonoids, including uptake transporters (such as organic anion transporter polypeptides (OATPs),157, 158 monocarboxylate transporter 1 (MCT1),159 organic anion transporters (OATS),160 urate anion transporter 1 (URAT1),161 and intestinal facilitated glucose transporter (GLUT2)162 among others).…”

Metabolic Effects of Mulberry Leaves: Exploring Potential Benefits in Type 2 Diabetes and Hyperuricemia

“…Various constituents of the drug were found to have significant antihyperuricemic potential, including mulberroside A, a stilbene glycoside [21], and a number of flavonoids, primarily morin [22, 23]. …”