Orotic acid transport via organic anion transporters OATs.

DOI 2 Citations 12 References
  • Anzai Naohiko
    Department of Pharmacology and Toxicology, Kyorin University School of Medicine
  • Miura Daisak-u
    Department of Pharmacology and Toxicology, Kyorin University School of Medicine Faculty of Pharmacy, Hyogo University of Medical Sciences
  • Endou Hitoshi
    Department of Pharmacology and Toxicology, Kyorin University School of Medicine J-Pharma Co. Inc.

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  • 有機アニオントランスポーターOAT4によるオロト酸輸送

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Orotic acid, a normal intermediate in pyrimidine synthesis, is converted to uridine 5'-triphosphate (UTP)that is utilized for the sythesis of RNA and for uridine diphosphosugars (UDP sugars) used in the glycosylation of basement membrane collagen. Therefore, as a precursor of uridine nucleotides, orotic acid incorporation is an important factor in glomerular and tubular basement membrane thickening, for example, observed in diabetes-induced renal hypertrophy. Orotic acid uptake is observed in normal liver and kidney, but its molecular mechanism is largely unknown. Because orotic acid is classified as a monocarboxylate, it requires specific pathway (s) such as the use of transporters to cross the plasma membrane. Therefore, we investigated whether human organic anion transporters (OATs) mediates the transport of orotic acid using mouse renal proximal tubule derived S2 cells stably expressing hOATs (S2-OAT2). Among OAT isoforms, we found that organic anion transporter 4 (OAT4) mediate the transport of orotic acid. Human OAT4 mediated the time- and dose-dependent uptake of orotic acid, with Km values of 922μM. OAT4-mediated orotic acid transport was inhibited strongly by steroid sulfates such as estrone sulfate and DHEA sulfate, probenecid and benzbromarone, and weakly by orotic acid, uric acid, salicylic acid, and PAH. These findings suggest that human OAT4 mediates the transport of orotic acid, and may function as one of its entrance pathways into renal proximal tubular cells.

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