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Drug Metabolism and Disposition Fast Forward
First published on February 26, 2007; DOI: 10.1124/dmd.106.012187

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Received for publication July 24, 2006.
Revised February 21, 2007.
Accepted for publication February 22, 2007.

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

Zhifeng Yu 1, Wing Ping Fong 1, Christopher H.K. Cheng 1*

1 The Chinese University of Hong Kong

* Address correspondence to: E-mail: chkcheng{at}cuhk.edu.hk

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 are 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 which 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 RT-PCR 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 IC50 value of the inhibition by morin was determined to be 2.0 µM, as compared to 50 µM for probenecid, 100 µM for sulfinpyrazone and 0.3 µM 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 Ki value of 5.74 µM.


Key words: cellular transport, drug development, drug discovery, renal transport, transporters


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