Human Organic Anion Transporters and Human Organic Cation Transporters Mediate Renal Transport of Prostaglandins
- Hiroaki Kimura2,
- Michio Takeda1,
- Shinichi Narikawa1,
- Atsushi Enomoto1,
- Kimiyoshi Ichida2 and
- Hitoshi Endou1
- 1Department of Pharmacology and Toxicology, Kyorin University School of Medicine, Tokyo, Japan (M.T., S.N., A.E., H.E.); and 2Division of Nephrology and Hypertension, Department of Internal Medicine, Jikeikai University School of Medicine, Tokyo, Japan (H.K., K.I.)
- Dr. Hitoshi Endou, Department of Pharmacology and Toxicology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka-shi, Tokyo 181, Japan. E-mail:endouh{at}kyorin-u.ac.jp
Abstract
Prostaglandin E2 (PGE2) and prostaglandin F2α (PGF2α) 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 PGE2 and PGF2α. The purpose of this study was to elucidate the molecular mechanism of renal PGE2 and PGF2α 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 PGE2 and PGF2αuptake was observed in cells expressing hOAT1, hOAT2, hOAT3, hOAT4, hOCT1, and hOCT2. The Km values of PGE2 uptake by hOAT1, hOAT2, hOAT3, hOAT4, hOCT1, and hOCT2 were 970, 713, 345, 154, 657, and 28.9 nM, respectively, whereas those of PGF2α uptake by hOAT1, hOAT3, hOAT4, hOCT1, and hOCT2 were 575, 1092, 692, 477, and 334 nM, respectively. PGE2and PGF2α 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 PGE2 and PGF2α 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.
Footnotes
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This study was supported in part by grants-in-aid from the Ministry of Education, Culture, Sports, Science and Technology (11671048, 11694310, and 13671128), the Science Research Promotion Fund of the Japan Private School Promotion Foundation, and Research on Health Sciences Focusing on Drug Innovation from Japan Health Sciences Foundation.
- Abbreviations:
- PG
- prostaglandin
- OAT
- organic anion transporter
- OCT
- organic cation transporter
- hOAT
- human OAT
- hOCT
- human OCT
- PAH
- para-aminohippuric acid
- ES
- estrone sulfate
- D-PBS
- Dulbecco's modified phosphate-buffered saline
- TEA
- tetraethylammonium
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- Received October 10, 2001.
- Accepted December 27, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
