Interactions of urate transporter URAT1 in human kidney with uricosuric drugs

Shin, Ho Jung; Takeda, Michio; Enomoto, Atsushi; Fujimura, Masaaki; Miyazaki, Hiroyuki; Anzai, Naohiko; Endou, Hitoshi

doi:10.1111/j.1440-1797.2010.01368.x

Cited by 98 publications

(71 citation statements)

References 23 publications

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“…20) It is also an important determinant charging of urate reabsorption from the lumen to the cytosolin kidney tubules, and a therapeutic target inhibited by some uricosuric agents, such as probenecid and benzbromarone. 21) GLUT9, localized in basolateral membranes of renal proximal tubule cells, is another urate transporter involved in urate reabsorption from the cytosolin kidney tubules to the interstitiumin a voltage-dependent manner. 22) The presence of GLUT9 mutations lead to losing the function of the protein, and in subsequence to hypouricemia, as well as increased FEUA.…”

Section: Discussionmentioning

confidence: 99%

Mangiferin Inhibits Renal Urate Reabsorption by Modulating Urate Transporters in Experimental Hyperuricemia

Yang

Gao

Niu

et al. 2015

Biological & Pharmaceutical Bulletin

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Mangiferin, a natural glucosyl xanthone from the leaves of Mangifera indica L., was previously shown to exert potent hypouricemic effects associated with inhibition of the activity of xanthine dehydrogenase/ oxidase. The present study aimed to evaluate its uricosuric effect and possible molecular mechanisms underlying the renal urate transporters responsible for urate reabsorption in vivo. Mangiferin (1.5-24.0 mg/kg) was administered intragastrically to hyperuricemic mice and rats induced by the intraperitoneal injection of uric acid and potassium oxonate, respectively. The uricosuric effect was evaluated by determining the serum and urinary urate levels as well as fractional excretion of uric acid (FEUA). The mRNA and protein levels of renal urate-anion transporter 1 (URAT1), organic anion transporter 10 (OAT10), glucose transporter 9 (GLUT9), and PDZ domain-containing protein (PDZK1) were analyzed. The administration of mangiferin significantly decreased the serum urate levels in hyperuricemic mice in a dose-and time-dependent manner. In hyperuricemic rats, mangiferin also reduced the serum urate levels and increased the urinary urate levels and FEUA. These results indicate that mangiferin has uricosuric effects. Further examination showed that mangiferin markedly inhibited the mRNA and protein expression of renal URAT1, OAT10, and GLUT9 in hyperuricemic rats, but did not interfere with PDZK1 expression. Taken together, these findings suggest that mangiferin promotes urate excretion by the kidney, which may be related to the inhibition of urate reabsorption via downregulation of renal urate transporters.

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Section: Discussionmentioning

confidence: 99%

Mangiferin Inhibits Renal Urate Reabsorption by Modulating Urate Transporters in Experimental Hyperuricemia

Yang

Gao

Niu

et al. 2015

Biological & Pharmaceutical Bulletin

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“…Uptake experiments were performed as previously described [10]. The cells were seeded in 24-well tissue culture plates at a density of 1.6 9 10 5 cells/well.…”

Section: Uptake Experimentsmentioning

confidence: 99%

Human urate transporter 1 (hURAT1) mediates the transport of orotate

et al. 2011

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Orotate is a precursor of pyrimidine synthesis. The kidney uses exogenous orotate for the synthesis of uridine diphosphosugars, which are used in the glycosylation of collagen in glomerular and tubular basement membranes. Orotate uptake occurs in the liver and kidney, but its molecular mechanism is largely unknown. Since orotate has been shown to be a substrate of the renal urate/anion exchanger in brush border membrane vesicle studies, we investigated whether human URAT1 (hURAT1) mediates the transport of orotate using HEK293 cells expressing hURAT1 (HEK-hURAT1). hURAT1 mediated a time- and dose-dependent uptake of orotate (K (m) 5.2 μM). hURAT1-mediated [(3)H]orotate transport was inhibited strongly by non-labeled (cold) orotate and the uricouric agent benzbromarone, and moderately inhibited by urate, nicotinate, and another uricouric agent, probenecid. This is the first report demonstrating that hURAT1 mediates the transport of orotate. hURAT1 may function as one of the entrance pathways in renal proximal tubular cells.

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“…Benzbromarone (BBR) is a benzofuran derivative (as shown in Fig. 1) that acts as a uricosuric agent by inhibiting urate reabsorption (Shin et al, 2011). Both BBR and 6-hydroxy BBR (a metabolite of BBR) have been reported to show potent human uric acid transporter 1 inhibition property (Wempe et al, 2011), which has made BBR a quite useful antigout agent for approximately 30 years in many countries.…”

Section: Introductionmentioning

confidence: 99%

Identification of Epoxide-Derived Metabolite(s) of Benzbromarone

Wang

Peng

et al. 2016

Drug Metabolism and Disposition

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Benzbromarone (BBR) is a benzofuran derivative that has been quite useful for the treatment of gout; however, it was withdrawn from European markets in 2003 because of reported serious incidents of drug-induced liver injury. BBR-induced hepatotoxicity has been suggested to be associated with the formation of a quinone intermediate. The present study reported epoxide-derived intermediate(s) of BBR. An N-acetylcysteine (NAC) conjugate derived from epoxide metabolite(s) was detected in both microsomal incubations of BBR and urine samples of mice treated with BBR. The NAC conjugate was identified as 6-NAC BBR. Ketoconazole suppressed the bioactivation of BBR to the epoxide intermediate(s), and the CYP3A subfamily was the primary enzyme responsible for the formation of the epoxide(s). The present study provided new information on metabolic activation of BBR.

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Interactions of urate transporter URAT1 in human kidney with uricosuric drugs

Cited by 98 publications

References 23 publications

Mangiferin Inhibits Renal Urate Reabsorption by Modulating Urate Transporters in Experimental Hyperuricemia

Mangiferin Inhibits Renal Urate Reabsorption by Modulating Urate Transporters in Experimental Hyperuricemia

Human urate transporter 1 (hURAT1) mediates the transport of orotate

Identification of Epoxide-Derived Metabolite(s) of Benzbromarone

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