title: Human urate transporter 1 (hURAT1) mediates the transport of orotate.
abstract: 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.
authors.affiliation: Department of Pharmacology and Toxicology, Kyorin University School of Medicine, 6-20-2, Shinkawa, Mitaka, Tokyo, 181-8611, Japan.
authors.forename: Daisaku
authors.initials: D
authors.lastname: Miura
authors.forename: Naohiko
authors.initials: N
authors.lastname: Anzai
authors.forename: Promsuk
authors.initials: P
authors.lastname: Jutabha
authors.forename: Suparat
authors.initials: S
authors.lastname: Chanluang
authors.forename: Xin
authors.initials: X
authors.lastname: He
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Fukutomi
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Endou
mesh_terms: D000818:Animals; D001553:Benzbromarone / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D002352:Carrier Proteins / Q000378:metabolism; D002478:Cells, Cultured; D057809:HEK293 Cells; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D009865:Oocytes; D027361:Organic Anion Transporters / Q000378:metabolism*; D027701:Organic Cation Transport Proteins / Q000378:metabolism*; D009963:Orotic Acid / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014527:Uric Acid / Q000378:metabolism; D014528:Uricosuric Agents / Q000494:pharmacology; D014981:Xenopus
chemical_list: D002352:Carrier Proteins; D027361:Organic Anion Transporters; D027701:Organic Cation Transport Proteins; C491241:SLC22A12 protein, human; D014528:Uricosuric Agents; D014527:Uric Acid; D001553:Benzbromarone; D009963:Orotic Acid