title: Organic anion transporter OAT1 is involved in renal handling of citrulline.
abstract: Because citrulline plasma concentration is elevated in kidney failure, citrulline could be a biomarker of renal insufficiency, although the mechanism regulating its disposition in the kidney has not been clarified. In rat kidney slices, citrulline uptake was apparently Na(+) dependent, saturable with K(m) 556 microM, and significantly inhibited by anionic (PAH) and cationic (TEA) compounds, but not by probenecid at 1 mM. Preincubation of kidney slices with glutarate increased citrulline uptake, while such an increase was not observed after preincubation of the slices in Na(+)-free buffer. This result suggested that a sodium-dependent dicarboxylate cotransporter is involved in citrulline uptake by rat kidney slices. In studies using transporter-overexpressing cells, human organic anion transporter 1 (OAT1) and rat Oat1 exhibited citrulline transport activity with K(m) values of 238 and 373 microM, respectively, while other OATs and organic cation transporters (OCTs) did not transport citrulline. Based on the relative activity factor method, the contribution of rat Oat1 to the overall uptake of citrulline in rat kidney slices was approximately 70%. Moreover, the interaction among citrulline, PAH, and probenecid uptakes via rat Oat1 suggested that there are multiple functional sites on Oat1 and that the citrulline site may be distinct from the PAH and probenecid site. Thus OAT1/Oat1 appears to be one of the major contributors to renal basolateral uptake of citrulline, and impaired activities of these transporters may contribute substantially to the increase in plasma citrulline in renal failure. Accordingly, citrulline may be useful for diagnosis of kidney function as is creatinine.
authors.affiliation: Department of Membrane Transport and Pharmacokinetics, Faculty of Pharmaceutical Sciences, Tokyo University ofScience, Tokyo, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Nakakariya
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Shima
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Shirasaka
authors.forename: Keisuke
authors.initials: K
authors.lastname: Mitsuoka
authors.forename: Takeo
authors.initials: T
authors.lastname: Nakanishi
authors.forename: Ikumi
authors.initials: I
authors.lastname: Tamai
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D050482:Catecholamine Plasma Membrane Transport Proteins / Q000378:metabolism; D002437:Cefazolin / Q000494:pharmacology; D002460:Cell Line; D002956:Citrulline / Q000378:metabolism*; D005977:Glutarates / Q000494:pharmacology; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D023421:Models, Animal; D050811:Octamer Transcription Factor-1 / Q000378:metabolism; D050813:Octamer Transcription Factor-2 / Q000378:metabolism; D027362:Organic Anion Transport Protein 1 / Q000378:metabolism*; D011339:Probenecid / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D010130:p-Aminohippuric Acid / Q000494:pharmacology
chemical_list: D050482:Catecholamine Plasma Membrane Transport Proteins; D005977:Glutarates; D050811:Octamer Transcription Factor-1; D050813:Octamer Transcription Factor-2; D027362:Organic Anion Transport Protein 1; C494165:POU2F1 protein, human; C493212:Slc22a1 protein, rat; C421043:Slc22a6 protein, rat; D002956:Citrulline; D002437:Cefazolin; D011339:Probenecid; D010130:p-Aminohippuric Acid