Naslov
OAT/OCT species and gender differences

Autori
Burckhardt, Gerhard ; Sabolić, Ivan

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
Final Programme and Abstracts / Annika Nyman, EUFEPS Secretariat - Stockholm : EUFEPS, 2006, 31-33

Skup
EUFEPS Conference on Membrane Drug Transporters: Impact on Drug Discovery, Development, Regulation and Usage

Mjesto i datum
Kopenhagen, Danska, 25.09.2006. - 27.09.2006

Vrsta sudjelovanja
Predavanje

Vrsta recenzije
Nije recenziran

Ključne riječi
organic anion transporters; organic cation transporters; kidney; liver

Sažetak
Organic anion and organic cation transporters (OATs, OCTs) belong to the SCL22 gene family of drug transporters exhibiting a broad substrate specificity [1]. OATs interact with ß-lactam antibiotics, antihypertensives, analgesics, diuretics, uricosurics and antiviral drugs [2], whereas OCTs handle adrenoceptor antagonists and agonists, histamine receptor antagonists, cation channel blockers, antidepressants, HIV protease inhibitors, and antidiabetics [3]. OAT1 is expressed at the basolateral membrane of renal proximal tubules. In rats, OAT1 is located mainly in S2 [4, 5], in mice in S1 and S2 [6], and in man in all three (S1-S3) proximal tubule segments [7]. Male rats and mice express more OAT1 than females [5, 8], whereas in rabbits the expression is gender-independent [8]. It is unknown whether gender differences exist in humans. OAT1 exchanges extracellular organic anions against intracellular alpha-ketoglutarate. OAT2 is expressed in kidneys and liver. In renal proximal tubules, OAT2 is located at the luminal membrane of S3 segments in rats and mice [9, 10], and at the basolateral membrane in humans [11]. Female rats and mice exhibit higher expression of OAT2 in kidneys [10] and liver [12]. The mode of transport of OAT2 is unresolved. OAT3 was located to the basolateral membrane in whole proximal tubule in rats, mice, and humans, as well as in downstream nephron segments in rats and mice [5-7, 13]. Gender differences were restricted to kidney cortex with male rats showing higher protein expression than females [5]. In rat liver, OAT3 is expressed much more in male rats (unpublished data). OAT3 exchanges organic anions against alpha-ketoglutarate. OAT4 is found only in humans where it is localized at the apical membranes of proximal tubules [14] and placenta [15]. It is unknown whether gender differences exist in kidneys. OAT4 functions as organic anion/ chloride and urate/ hydroxyl ion exchanger and contributes to secretion of diuretics [16]. Proximal tubular urate absorption is largely mediated by the urate/ lactate antiporter URAT1, located at the apical membrane [17]. In mice, Urat1 or Rst is also located at the brush-border membrane of proximal tubules and shows higher expression in male than in female animals [18]. Similar gender differences may be present in humans. OCT1 - OCT3 utilize the inside negative membrane potential as driving force for cation uptake. OCT1 shows clear species differences: it is expressed in renal proximal tubules in rodents (segments S1 and S2), but not in humans [19, 20]. In all tested species, OCT1 is present in the liver, but gender differences in its expression are not known. OCT2 is located at the basolateral membrane of proximal tubules in rodent (segments S2, S3) and human kidneys (all segments) [7, 19]. In rat liver, OCT2 is located at the sinusoidal membrane of hepatocytes [21]. In rat kidneys, OCT2 is expressed more in male than in female animals [22]. Rabbits, however, exhibit no gender differences in the renal OCT2 protein abundance [8]. No such data are available for humans. OCT3 is ubiquitously expressed, including in the central nervous system, where it may be involved in the uptake of neurotransmitters [3]. Renal expression of OCT3 is higher in humans than in rats and mice [3]. No gender differences were found in rat kidneys [22]. Taken together, OATs and OCTs show species differences with respect to their localization along the nephron (OAT1, OAT3, OCT1, OCT2) and at the subcellular level (OAT2). In addition, gender differences exist – at least in rats and mice – for most of the OATs and OCTs, indicating possible species- and gender-dependent pharmacokinetics of various drugs. References 1. Koepsell H, Endou H. The SLC22 drug transporter family. Pflügers Arch – Eur J Physiol 2004 ; 447 ; 666-676. 2. Burckhardt BC, Burckhardt G. Transport of organic anions across the basolateral membrane of proximal tubule cells. Rev Physiol Biochem Pharmacol 2003 ; 146:95-158. 3. Koepsell H, Schmitt BM, Gorboulev V. Organic cation transporters. Rev Physiol Biochem Pharmacol 2003 ; 150:36-90. 4. Tojo A, Sekine T, NakajimaN et al. Immunohistochemical localization of multispecific renal organic anion transporter 1 in rat kidney. J Am Soc Nephrol 1999 ; 10:464-471 5. Ljubojevic M, Herak-Kramberger CM, Hagos Y et al. Am J Physiol Renal Physiol 2004 ; 287:F124-F138 6. Bahn A, Ljubojevic M, Lorenz H et al. Murine renal organic anion transporters mOAT1 and mOAT3 facilitate the transport of neuroactive tryptophan metabolites. Am J Physiol Cell Physiol 2005 ; 298:C1075-C1084 7. Motohashi H, Sakurai Y, Saito H et al. Gene expression levels and immunolocalization of organic ion transporters in human kidney. J Am Soc Nephrol 2002 ; 13:866-874 8. Groves CE, Suhre WB, Cherrington NJ, Wright SH. Sex differences in the mRNA, protein, and functional expression of organic anion transporter (Oat) 1, Oat3, and organic cation transporter (Oct) 2 in rabbit renal proximal tubules. J Pharmacol Exp Ther 2006 ; 316:743-752 9. Kobayashi Y, Ohbayashi M, Kohyama N, Yamamoto T. Mouse organic anion transporter 2 and 3 (mOAT2/3[Slc22a7/8]) mediated the renal transport of bumetanide. Eur J Pharmacol 2005 ; 524:44-44 10. Ljubojevic M, Balen D, Breljak D et al. Renal expression of organic anion transporter OAT2 in rats and mice is regulated by sex hormones. Am J Physiol Renal Physiol, submitted 11. Enomoto A, Takeda M, Shimoda M et al. Interaction of human organic anion transporters 2 and 4 with organic anion transport inhibitors. J Pharmacol Exp Ther 2002 ; 301:797-802 12. Kobayashi Y, Oshiro N, Shibusawa A et al. Isolation, characterization and differential gene expression of multispecific organic anion transporter 2 in mice. Mol Pharm 2002 ; 62:7-14. 13. Kojima R, Sekine T, Kawachi M et al. Immunolocalization of multispecific organic anion transporters, OAT1, OAT2, and OAT3, in rat kidney. J Am Soc Nephrol 2002 ; 13:848-857 14. Ekaratanawong S, Anzai N, Jutabha P et al. Human organic anion transporter 4 is a renal apical organic anion/dicarboxylate exchanger in the proximal tubules. J Pharmacol Sci 2004 ; 94:297-304 15. Ugele B, St-Pierre MV, Pihusch M et al. Characterization and identification of steroid sulfate transporters in human placenta. Am J Physiol Endocrin 2003 ; 284:E390-E398 16. Hagos Y, Stein D, Ugele B et al. Human renals organic-anion-transporter 4 (hOAT4) operates as an asymmetric urate transporter. J Am Soc Nephrol, submitted 17. Enomoto A, Kimura H, Chairoungdua A et al. Molecular identification of a renal urate-anion exchanger that regulates blood urate levels. Nature 2002 ; 417:447-452 18. Hosoyamada M, Ichida K, Enomoto A et al. Function and localization of urate transporter 1 in mouse kidney. J Am Soc Nephrol 2004 ; 15:261-268 19. Karbach U, Kricke J, Meyer-Wentrup F et al. Localization of organic cation transporters OCT1 and OCT2 in rat kidney. Am J Physiol Renal Physiol 2000 ; 279:F679-F687 20. Gorboulev V, Ulzheimer JC, Akhoundova A et al. Cloning and characterization of two human polyspecific organic cation transporters. DNA Cell Biol 1997 ; 16:871-881 21. Meyer-Wentrup F, Karbach U, Gorboulev V et al. Membrane localization of the electrogenic cation transporter rOCT1 in rat liver. Biochem Biophys Res Commun 1998 ; 248:673-678 22. Urakami Y, Nakamura N, Takashi K et al. Gender differences in expression of organic cation transporter OCT2 in rat kidney. FEBS Lett 1999 ; 461:339-342

Izvorni jezik
Engleski

Znanstvena područja
Temeljne medicinske znanosti

POVEZANOST RADA