Human Organic Anion Transporters and Human Organic Cation Transporters Mediate Renal Transport of Prostaglandins

Abstract

Prostaglandin E 2 (PGE 2 ) and prostaglandin F 2␣ (PGF 2␣ ) have been used for the induction of labor and the termination of pregnancy. Renal excretion is shown to be an important pathway for the elimination of PGE 2 and PGF 2␣ . The purpose of this study was to elucidate the molecular mechanism of renal PGE 2 and PGF 2␣ transport using cells stably expressing human organic anion transporter (hOAT) 1, hOAT2, hOAT3, and hOAT4, and human organic cation transporter (hOCT) 1 and hOCT2. A time-and dose-dependent increase in PGE 2 and PGF 2␣ uptake was observed in cells expressing hOAT1, hOAT2, hOAT3, hOAT4, hOCT1, and hOCT2. The K m values of PGE 2 uptake by hOAT1, hOAT2, hOAT3, hOAT4, hOCT1, and hOCT2 were 970, 713, 345, 154, 657, and 28.9 nM, respectively, whereas those of PGF 2␣ uptake by hOAT1, hOAT3, hOAT4, hOCT1, and hOCT2 were 575, 1092, 692, 477, and 334 nM, respectively. PGE 2 and PGF 2␣ significantly inhibited organic anion uptake by hOATs and organic cation uptake by hOCTs. In conclusion, considering the localization of these transporters, the results suggest that PGE 2 and PGF 2␣ transport in the basolateral membrane of the proximal tubule is mediated by multiple pathways including hOAT1, hOAT2, hOAT3, and hOCT2, whereas that in the apical side is mediated by hOAT4.

Prostaglandin E2 Inhibits Its Own Renal Transport by Downregulation of Organic Anion Transporters rOAT1 and rOAT3

“…Thus, the expected concentration of free PGE 2 is likely to be in a range that suffices to generate an effect on OAT1 and OAT3. PGE 2 is a substrate for both OAT mentioned (14). With respect to a role of peripheral PGE 2 in fever (as suggested by Ivanov et al [19]), it would make sense that renal clearance is impaired together with metabolic clearance to achieve high plasma levels of PGE 2 .…”

“…Because of protein binding, proximal tubular secretion of PGE 2 plays a major role in renal excretion (22). Because PGE 2 is a substrate for both OAT1 and OAT3 (14), these transporters represent the rate-limiting basolateral uptake step of proximal tubule PGE 2 secretion. Therefore, it seems reasonable to speculate that renal secretion of PGE 2 also could be impaired in the above-mentioned fever model.…”

“…Prostaglandin E 2 (PGE 2 ) is a substrate for both OAT1 and OAT3 (14) and is considered to be the principal downstream mediator of fever (15). In general, fever-generating PGE 2 is thought to be produced in the brain (16).…”

Novel liver-specific organic anion transporter OAT7 that operates the exchange of sulfate conjugates for short chain fatty acid butyrate

“…6 For sodium-independent uptake, organic anion-transporting polypeptides (OATPs) of the SLC21 (SLC0) family, such as OATP-B, 7,8 OATP-C, [9][10][11] and OATP8, 12,13 mediate the transport of a variety of organic anions such as sulfobromophthalein, bile salts, and sulfate-conjugated steroid hormones, although their driving forces are still unclear. In addition, organic anion transporter 2 (OAT2) in the SLC22 family mediates the transport of organic anion such as para-aminohippurate, 14 prostaglandins, 15 zidovudine, 16 tetracycline, 17 and salicylates 18 in a sodium-independent manner. Recently, Kobayashi et al 19 have reported that it also mediates the transport of steroid sulfates as well as several drugs.…”

EZH2 Inhibitor GSK126: Metabolism, drug transporter and rat pharmacokinetic studies

“…From transgenic mice harboring the simian virus 40 large Tantigen gene, S2-hOAT1, S2-hOAT2, S2-hOAT3, and S2-hOAT4 were established and characterized as previously reported Hosoyamada et al, 1996;Takeda et al, 2002;Kimura et al, 2002). Briefly, the full-length cDNAs of hOATs were sub-cloned into pcDNA 3.1 (Invitrogen), a mammalian expression vector.…”