2.A.60 The Organo Anion Transporter (OAT) Family

Proteins of the OAT family (solute carrier family 21 (previously called SLC21A; more recently designated SLCO by the HUGO Gene Nomenclature Committee (B. Hagenbuch, personal communication))) catalyze the Na+-independent facilitated transport of fairly large amphipathic organic anions (and less frequently neutral or cationic drugs) such as bromosulfobromophthalein, prostaglandins, conjugated and unconjugated bile acids (taurocholate and cholate, respectively), steroid conjugates such as estrone-sulfate and dehydroepiandrosterone-sulfate (Rižner et al. 2017), thyroid hormones, anionic oligopeptides, drugs, toxins and other xenobiotics (Hong 2013).  Among the well characterized substrates are numerous drugs including statins, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, antibiotics, antihistaminics, antihypertensives and anticancer drugs (Hagenbuch and Stieger 2013).  There are six mammalian OAT families (Hagenbuch and Stieger 2013).  Fluorescein is a general OAT family substrate (Patik et al. 2015), but Hagenbuch and Gui 2008 have summarized the general features and substrates of the eleven human OATPs, and Jetter and Kullak-Ublick 2019 have summarized the interplay between various transporters of drugs, xenobiotics and bile salts.

The various paralogues in a mammal have differing but overlapping substrate specificities and tissue distributions as summarized by Hagenbuch and Meier (2003). These authors also provide a phylogenetic tree of the mammalian members of the family, showing that they fall into five recognizable subfamilies, four of which exhibit deep branching sub-subfamilies. However, all sequences within a subfamily are >60% identical while those between subfamilies are >40% identical (Hagenbuch and Meier, 2003). Therefore, these mammalian proteins are all included within a single subfamily of the TC system (TC #2.A.60.1). The detailed substrates transported and their affinities are presented by Hagenbuch and Meier (2003). As also shown by Hagenbuch and Meier, all but one (OatP4a1) of the mammalian homologues cluster together, separately from all other animal (insect and worm) homologues. OAT family homologues have been found in other animals but not outside of the animal kingdom.

These transporters have been characterized primarily in mammals, but characterized homologues are present in D. melanogaster (Eraly et al. 2004; Chahine et al. 2012), A. gambiae, and C. elegans. The mammalian OAT family proteins exhibit a high degree of tissue specificity. Mammalian homologues consist of 640-722 amino acyl residues and possess 12 putative α-helical transmembrane spanners. They may catalyze electrogenic anion uniport or more frequently, anion exchange. Conformational changes of the multispecific organic anion transporter 1 (OAT1/SLC22A6) has suggested a molecular mechanism for initial stages of drug and metabolite transport (Tsigelny et al., 2011). The OAT family is a distant family within the MFS (TC #2.A.1). Regulation of expression and function of OATps has been described (Svoboda et al., 2011).

The generalized transport reaction catalyzed by members of the OAT family is:

Anion (in) → Anion (out)

or

Anion1 (in) + Anion2 (out) → Anion1 (out) + Anion2 (in).



This family belongs to the MFS Superfamily.

 

References:

Hong M. (2014). Critical domains within the sequence of human organic anion transporting polypeptides. Curr Drug Metab. 15(3):265-70.



Abdullahi, W., T.P. Davis, and P.T. Ronaldson. (2017). Functional Expression of P-glycoprotein and Organic Anion Transporting Polypeptides at the Blood-Brain Barrier: Understanding Transport Mechanisms for Improved CNS Drug Delivery? AAPS J 19: 931-939.

Abe, T., M. Kakyo, H. Sakagami, T. Tokui, T. Nishio, M. Tanemoto, H. Nomura, S.C. Hebert, S. Matsuno, H. Kondo, and H. Yawo. (1998). Molecular characterization and tissue distribution of a new organic anion transporter subtype (Oatp3) that transports thyroid hormones and taurocholate and comparison with Oatp2. J. Biol. Chem. 273: 22395-22401.

Abe, T., M. Kakyo, T. Tokui, R. Nakagomi, T. Nishio, D. Nakai, H. Nomura, M. Unno, M. Suzuki, T. Naitoh, S. Matsuno, and H. Yawo. (1999). Identification of a novel gene family encoding human liver-specific organic anion transporter LST-1. J. Biol. Chem. 274: 17159-17163.

Arakawa, H., Y. Shirasaka, M. Haga, T. Nakanishi, and I. Tamai. (2012). Active intestinal absorption of fluoroquinolone antibacterial agent ciprofloxacin by organic anion transporting polypeptide, Oatp1a5. Biopharm Drug Dispos 33: 332-341.

Bernal J., Guadano-Ferraz A. and Morte B. (2015). Thyroid hormone transporters--functions and clinical implications. Nat Rev Endocrinol. 11(7):406-17.

Bian, J., M. Jin, M. Yue, M. Wang, H. Zhang, and C. Gui. (2016). Tryptophan Residue Located at the Middle of Putative Transmembrane Domain 11 Is Critical for the Function of Organic Anion Transporting Polypeptide 2B1. Mol Pharm. [Epub: Ahead of Print]

Brennan, B.J., A. Poirier, S. Moreira, P.N. Morcos, P. Goelzer, R. Portmann, J. Asthappan, C. Funk, and P.F. Smith. (2015). Characterization of the transmembrane transport and absolute bioavailability of the HCV protease inhibitor danoprevir. Clin Pharmacokinet 54: 537-549.

Briz, O., M.R. Romero, P. Martinez-Becerra, R.I. Macias, M.J. Perez, F. Jimenez, F.G. San Martin, and J.J. Marin. (2006). OATP8/1B3-mediated cotransport of bile acids and glutathione: an export pathway for organic anions from hepatocytes? J. Biol. Chem. 281: 30326-30335.

Cai, S.Y., W. Wang, C.J. Soroka, N. Ballatori, and J.L. Boyer. (2002). An evolutionarily ancient Oatp: insights into conserved functional domains of these proteins. Am. J. Physiol. Gastrointest Liver Physiol 282: G702-710.

Chahine, S., S. Seabrooke, and M.J. O'Donnell. (2012). Effects of genetic knock-down of organic anion transporter genes on secretion of fluorescent organic ions by Malpighian tubules of Drosophila melanogaster. Arch Insect Biochem Physiol 81: 228-240.

Chan, B.S., J.A. Satriano, M. Pucci, and V.L. Schuster. (1998). Mechanism of prostaglandin E2 transport across the plasma membrane of HeLa cells and Xenopus oocytes expressing the prostaglandin transporter "PGT". J. Biol. Chem. 273: 6689-6697.

Chi Y. and Schuster VL. (2010). The prostaglandin transporter PGT transports PGH(2). Biochem Biophys Res Commun. 395(2):168-72.

Cui, Y., J. König, I. Leier, U. Buchholz, and D. Keppler. (2001). Hepatic uptake of bilirubin and its conjugates by the human organic anion transporter SLC21A6. J. Biol. Chem. 276: 9626-9630.

DeGorter, M.K., R.H. Ho, B.F. Leake, R.G. Tirona, and R.B. Kim. (2012). Interaction of three regiospecific amino acid residues is required for OATP1B1 gain of OATP1B3 substrate specificity. Mol Pharm 9: 986-995.

Eraly, S.A., J.C. Monte, and S.K. Nigam. (2004). Novel slc22 transporter homologs in fly, worm, and human clarify the phylogeny of organic anion and cation transporters. Physiol Genomics 18: 12-24.

Fang, Z., J. Huang, J. Chen, S. Xu, Z. Xiang, and M. Hong. (2018). Transmembrane domain 1 of human organic anion transporting polypeptide 2B1 is essential for transporter function and stability. Mol Pharmacol. [Epub: Ahead of Print]

Gruetz, M., H. Sticht, H. Glaeser, M.F. Fromm, and J. König. (2016). Analysis of amino acid residues in the predicted transmembrane pore influencing transport kinetics of the hepatic drug transporter organic anion transporting polypeptide 1B1 (OATP1B1). Biochim. Biophys. Acta. 1858: 2894-2902. [Epub: Ahead of Print]

Gui, C. and B. Hagenbuch. (2008). Amino acid residues in transmembrane domain 10 of organic anion transporting polypeptide 1B3 are critical for cholecystokinin octapeptide transport. Biochemistry 47: 9090-9097.

Hagenbuch, B. (1997). Molecular properties of hepatic uptake systems for bile acids and organic acids. J. Membr. Biol. 160: 1-8.

Hagenbuch, B. and B. Stieger. (2013). The SLCO (former SLC21) superfamily of transporters. Mol Aspects Med 34: 396-412.

Hagenbuch, B. and C. Gui. (2008). Xenobiotic transporters of the human organic anion transporting polypeptides (OATP) family. Xenobiotica 38: 778-801.

Hagenbuch, B. and P.J. Meier. (2003). The superfamily of organic anion transporting polypeptides. Biochim. Biophys. Acta 1609: 1-18.

Hakes, D.J. and R. Berezney. (1991). Molecular cloning of matrin F/G: a DNA binding protein of the nuclear matrix that contains putative zinc finger motifs. Proc. Natl. Acad. Sci. USA 88: 6186-6190.

Herfindal, L., C. Krakstad, L. Myhren, H. Hagland, R. Kopperud, K. Teigen, F. Schwede, R. Kleppe, and S.O. Døskeland. (2014). Introduction of Aromatic Ring-Containing Substituents in Cyclic Nucleotides Is Associated with Inhibition of Toxin Uptake by the Hepatocyte Transporters OATP 1B1 and 1B3. PLoS One 9: e94926.

Hogg K., Thomas J., Ashford D., Cartwright J., Coldwell R., Weston DJ., Pillmoor J., Surry D. and O'Toole P. (2015). Quantification of proteins by flow cytometry: Quantification of human hepatic transporter P-gp and OATP1B1 using flow cytometry and mass spectrometry. Methods. 82:38-46.

Hong W., Wu Z., Fang Z., Huang J., Huang H. and Hong M. (2015). Amino Acid Residues in the Putative Transmembrane Domain 11 of Human Organic Anion Transporting Polypeptide 1B1 Dictate Transporter Substrate Binding, Stability, and Trafficking. Mol Pharm. 12(12):4270-6.

Hosotani, R., W. Inoue, T. Takemiya, K. Yamagata, S. Kobayashi, and K. Matsumura. (2015). Prostaglandin transporter in the rat brain: its localization and induction by lipopolysaccharide. Temperature (Austin) 2: 425-434.

Huang J., Li N., Hong W., Zhan K., Yu X., Huang H. and Hong M. (2013). Conserved tryptophan residues within putative transmembrane domain 6 affect transport function of organic anion transporting polypeptide 1B1. Mol Pharmacol. 84(4):521-7.

Jacquemin, E., B. Hagenbuch, B. Stieger, A.W. Wolkoff, and P.J. Meier. (1994). Expression cloning of a rat liver Na(+)-independent organic anion transporter. Proc. Natl. Acad. Sci. USA 91: 133-137.

Jetter, A. and G.A. Kullak-Ublick. (2019). Drugs and hepatic transporters: A review. Pharmacol Res. [Epub: Ahead of Print]

Kanai, N., R. Lu, J.A. Satriano, Y. Bao, A.W. Wolkoff, and V.L. Schuster. (1995). Identification and characterization of a prostaglandin transporter. Science 268: 866-869.

Kinne, A., R. Schülein, and G. Krause. (2011). Primary and secondary thyroid hormone transporters. Thyroid Res 4Suppl1: S7.

Li, N., W. Hong, H. Huang, H. Lu, G. Lin, and M. Hong. (2012). Identification of Amino Acids Essential for Estrone-3-Sulfate Transport within Transmembrane Domain 2 of Organic Anion Transporting Polypeptide 1B1. PLoS One 7: e36647.

Lofthouse EM., Brooks S., Cleal JK., Hanson MA., Poore KR., O'Kelly IM. and Lewis RM. (2015). Glutamate cycling may drive organic anion transport on the basal membrane of human placental syncytiotrophoblast. J Physiol. 593(20):4549-59.

Maeda, T., K. Takahashi, N. Ohtsu, T. Oguma, T. Ohnishi, R. Atsumi, and I. Tamai. (2007). Identification of influx transporter for the quinolone antibacterial agent levofloxacin. Mol. Pharm. 4: 85-94.

Malagnino, V., J. Hussner, I. Seibert, A. Stolzenburg, C.P. Sager, and H.E. Meyer Zu Schwabedissen. (2017). LST-3TM12 is a member of the OATP1B family and a functional transporter. Biochem Pharmacol. [Epub: Ahead of Print]

Mayerl, S., M. Schmidt, D. Doycheva, V.M. Darras, S.S. Hüttner, A. Boelen, T.J. Visser, C. Kaether, H. Heuer, and J. von Maltzahn. (2018). Thyroid Hormone Transporters MCT8 and OATP1C1 Control Skeletal Muscle Regeneration. Stem Cell Reports. [Epub: Ahead of Print]

Mikkaichi, T., T. Suzuki, T. Onogawa, M. Tanemoto, H. Mizutamari, M. Okada, T. Chaki, S. Masuda, T. Tokui, N. Eto, M. Abe, F. Satoh, M. Unno, T. Hishinuma, K. Inui, S. Ito, J. Goto, and T. Abe. (2004). Isolation and characterization of a digoxin transporter and its rat homologue expressed in the kidney. Proc. Natl. Acad. Sci. USA 101: 3569-3574.

Mulenga, A., R. Khumthong, K.C. Chalaire, O. Strey, and P. Teel. (2008). Molecular and biological characterization of the Amblyomma americanum organic anion transporter polypeptide. J Exp Biol 211: 3401-3408.

Navrátilová, L., L. Applová, P. Horký, P. Mladěnka, P. Pávek, and F. Trejtnar. (2018). Interaction of soy isoflavones and their main metabolites with hOATP2B1 transporter. Naunyn Schmiedebergs Arch Pharmacol. [Epub: Ahead of Print]

Nele Bourgeois, M.A., S.L. Van Herck, P. Vancamp, J. Delbaere, C. Zevenbergen, S. Kersseboom, V.M. Darras, and T.J. Visser. (2016). CHARACTERIZATION OF CHICKEN THYROID HORMONE TRANSPORTERS. Endocrinology en20152025. [Epub: Ahead of Print]

Ohkura, N., Y. Shigetani, N. Yoshiba, K. Yoshiba, and T. Okiji. (2014). Prostaglandin transporting protein-mediated prostaglandin E2 transport in lipopolysaccharide-inflamed rat dental pulp. J Endod 40: 1112-1117.

Patik I., Kovacsics D., Nemet O., Gera M., Varady G., Stieger B., Hagenbuch B., Szakacs G. and Ozvegy-Laczka C. (2015). Functional expression of the 11 human Organic Anion Transporting Polypeptides in insect cells reveals that sodium fluorescein is a general OATP substrate. Biochem Pharmacol. 98(4):649-58.

Patrick PS., Lyons SK., Rodrigues TB. and Brindle KM. (2014). Oatp1 enhances bioluminescence by acting as a plasma membrane transporter for D-luciferin. Mol Imaging Biol. 16(5):626-34.

Popovic, M., R. Zaja, K. Fent, and T. Smital. (2013). Molecular characterization of zebrafish Oatp1d1 (Slco1d1), a novel organic anion-transporting polypeptide. J. Biol. Chem. 288: 33894-33911.

Prestin, K., S. Wolf, R. Feldtmann, J. Hussner, I. Geissler, C. Rimmbach, H.K. Kroemer, U. Zimmermann, and H.E. Meyer zu Schwabedissen. (2014). Transcriptional regulation of urate transportosome member SLC2A9 by nuclear receptor HNF4α. Am. J. Physiol. Renal Physiol 307: F1041-1051.

Qi, X., E. Wagenaar, W. Xu, K. Huang, and A.H. Schinkel. (2017). Ochratoxin A transport by the human breast cancer resistance protein (BCRP), multidrug resistance protein 2 (MRP2), and organic anion-transporting polypeptides 1A2, 1B1 and 2B1. Toxicol Appl Pharmacol 329: 18-25.

Rižner, T.L., T. Thalhammer, and C. Özvegy-Laczka. (2017). The Importance of Steroid Uptake and Intracrine Action in Endometrial and Ovarian Cancers. Front Pharmacol 8: 346.

Schäfer, A.M., O. Potterat, I. Seibert, O. Fertig, and H.E. Meyer Zu Schwabedissen. (2019). Hyperforin-Induced Activation of the Pregnane X Receptor Is Influenced by the Organic Anion-Transporting Polypeptide 2B1. Mol Pharmacol 95: 313-323.

Schuster, V.L. (1998). Molecular mechanisms of prostaglandin transport. Annu. Rev. Physiol. 60: 221-242.

Schuster, V.L. (2002). Prostaglandin transport. Prostaglandins Other Lipid Mediat 68-69: 633-647.

Sugiyama, D., H. Kusuhara, H. Taniguchi, S. Ishikawa, Y. Nozaki, H. Aburatani, and Y. Sugiyama. (2003). Functional characterization of rat brain-specific organic anion transporter (Oatp14) at the blood-brain barrier. High affinity transporter for thyroxine. J. Biol. Chem. 278: 43489-43495.

Svoboda, M., J. Riha, K. Wlcek, W. Jaeger, and T. Thalhammer. (2011). Organic anion transporting polypeptides (OATPs): regulation of expression and function. Curr Drug Metab 12: 139-153.

Sweet, D.H., D.S. Miller, J.B. Pritchard, Y. Fujiwara, D.R. Beier, and S.K. Nigam. (2002). Impaired organic anion transport in kidney and choroid plexus of organic anion transporter 3 (Oat3 (Slc22a8)) knockout mice. J. Biol. Chem. 277: 26934-26943.

Tian J., Keller MP., Oler AT., Rabaglia ME., Schueler KL., Stapleton DS., Broman AT., Zhao W., Kendziorski C., Yandell BS., Hagenbuch B., Broman KW. and Attie AD. (2015). Identification of the Bile Acid Transporter Slco1a6 as a Candidate Gene That Broadly Affects Gene Expression in Mouse Pancreatic Islets. Genetics. 201(3):1253-62.

Tirona, R.G., B.F. Leake, G. Merino, and R.B. Kim. (2001). Polymorphisms in OATP-C. Identification of multiple allelic variants associated with altered transport activity among European- and African-Americans. J. Biol. Chem. 276: 35669-35675.

Tsigelny, I.F., D. Kovalskyy, V.L. Kouznetsova, O. Balinskyi, Y. Sharikov, V. Bhatnagar, and S.K. Nigam. (2011). Conformational changes of the multispecific transporter organic anion transporter 1 (OAT1/SLC22A6) suggests a molecular mechanism for initial stages of drug and metabolite transport. Cell Biochem Biophys 61: 251-259.

van de Steeg, E., V. Stránecký, H. Hartmannová, L. Nosková, M. Hřebíček, E. Wagenaar, A. van Esch, D.R. de Waart, R.P. Oude Elferink, K.E. Kenworthy, E. Sticová, M. al-Edreesi, A.S. Knisely, S. Kmoch, M. Jirsa, and A.H. Schinkel. (2012). Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver. J Clin Invest 122: 519-528.

van Montfoort, J.E., T.E. Schmid, I.-D. Adler, P.J. Meier, and B. Hagenbuch. (2002). Functional characterization of the mouse organic-anion-transporting polypeptide 2. Biochim. Biophys. Acta 1564: 183-188.

Wang, P., R.B. Kim, J.R. Chowdhury, and A.W. Wolkoff. (2003). The human organic anion transport protein SLC21A6 is not sufficient for bilirubin transport. J. Biol. Chem. 278: 20695-20699.

Wang, X., Y. Liang, Z. Fang, J. Huang, and M. Hong. (2019). The intracellular NPxY motif is critical in maintaining the function and expression of human organic anion transporting polypeptide 1B1. Biochim. Biophys. Acta. Biomembr 1861: 1189-1196.

Westholm, D.E., J.D. Marold, K.J. Viken, A.H. Duerst, G.W. Anderson, and J.N. Rumbley. (2010). Evidence of evolutionary conservation of function between the thyroxine transporter Oatp1c1 and major facilitator superfamily members. Endocrinology 151: 5941-5951.

Wu, M.R., H.M. Liu, C.W. Lu, W.H. Shen, I.J. Lin, L.W. Liao, Y.Y. Huang, M.J. Shieh, and J.K. Hsiao. (2018). Organic anion-transporting polypeptide 1B3 as a dual reporter gene for fluorescence and magnetic resonance imaging. FASEB J. 32: 1705-1715.

Yerushalmi, G.M., S. Markman, Y. Yung, E. Maman, S. Aviel-Ronen, R. Orvieto, E.Y. Adashi, and A. Hourvitz. (2016). The prostaglandin transporter (PGT) as a potential mediator of ovulation. Sci Transl Med 8: 338ra68.

Zada, D., E. Blitz, and L. Appelbaum. (2017). Zebrafish - An emerging model to explore thyroid hormone transporters and psychomotor retardation. Mol. Cell Endocrinol. [Epub: Ahead of Print]

Zhang, H.X., X. Zhao, Z. Yang, C.Y. Peng, R. Long, G.N. Li, J. Li, and Z.K. He. (2010). [OATP 1B1 T521C/A388G is an important polymorphism gene related to neonatal hyperbilirubinemia]. Zhonghua Er Ke Za Zhi 48: 650-655.

Zhang, Y., K.H. Boxberger, and B. Hagenbuch. (2017). Organic anion transporting polypeptide 1B3 can form homo- and hetero-oligomers. PLoS One 12: e0180257.

Examples:

TC#NameOrganismal TypeExample
2.A.60.1.1

Organic anion transporter, Oatp1 (SLC21A1) (substrates: digoxin, bromosulfophthalein, conjugated (taurocholate) and unconjugated (cholate) bile salts; conjugated and unconjugated steroid hormones, eicosanoids, peptides, drugs, toxins, other organic anions (e.g., bilirubin, glucuronide) and organic cations (e.g., N-methylquinidine, rocuronium)) (Na+-independent)

Animals

Oatp1 of Rattus norvegicus

 
2.A.60.1.10

Brain Oat14 (SLC21A14) (transports bidirectionally thyroxine (T4; prothyroid hormone; Km=0.2 μM), triiodothyronine (T3; Km=1.2 μM), amphipathic organic anions such as 17-β-estradiol-D-17-β-glucuronide (Km=10 μM), cerivastatin (Km=1 μM) and troglitazone (Km=0.8 μM)) (Sugiyama et al., 2003)

Animals

Oat14 of Rattus norvegicus (NP_445893)

 
2.A.60.1.11OATP4C1 kidney (basolateral membrane of proximal tubule cells), organic anion transporter (transports cardiac glycosides [digoxin, Km=8 μM; ouabain, Km= 0.4 μM], thyroid hormones (thyroxine and triiodothyronine), cAMP, and methotrexate (Mikkaichi et al., 2004)
AnimalsSLCO4C1 of Homo sapiens
 
2.A.60.1.12

OAT8/1B3 (SLC21A, SLCO1B3, LST2, OATP1B3) The bile acid (cholic acid)/glutathione (GSH:bile acid = 2.1) exporter (Briz et al., 2006). Also transports the octapeptide, cholecystokinin (CCK-8) (Gui and Hagenbuch, 2008) and danoprevir (hepatitis C virus protease inhibitor) (Brennan et al. 2015). Forms homo and hetero oligomers, but the monomer is the active species (Zhang et al. 2017). It has been used as a dual reporter gene for fluorescence and magnetic resonance imaging (Wu et al. 2018).  Mediates the Na+-independent uptake of organic anions such as 17-beta-glucuronosyl estradiol, taurocholate, triiodothyronine (T3), leukotriene C4, dehydroepiandrosterone sulfate (DHEAS), methotrexate and sulfobromophthalein (BSP). Involved in the clearance of bile acids and organic anions from the liver (van de Steeg et al. 2012).

Animals

SLCO1B3 of Homo sapiens

 
2.A.60.1.13Liver anion transporter OatP of the little skate (689aas) (Cai et al., 2002)AnimalsOatP of Leucoraja (Raja) erinacea (Q8UVG4)
 
2.A.60.1.14

The Na+-independent organic anion transporter, OATP-A (OatP1, Oat1A2, OatP1A2, SLC21A3, SLCO1A2 of 670 aas).  Transports various anions such as cholate and taurocholate as well as the quinolone antibacterial agent levofloxacin and Ochratoxin (Ota) (Maeda et al., 2007; Qi et al. 2017). Also transports thyroid hormones. The transport of primary and secondary thyroid hormone transporters has been reviewed (Kinne et al., 2011).  Transports luciferin, the substrate of luciferase (Patrick et al. 2014).

Animals

SLCO1A2 of Homo sapiens

 
2.A.60.1.15

OAT family 1C1 protein, isoform 1, Oatp1c1; transports thyroid horomone and other organic anions (Westholm et al. 2010). (83% identical to 2.A.60.1.10). Primary and secondary thyroid hormone transporters have been reviewed (Kinne et al., 2011) and (Bernal et al. 2015). Together with MTC8 (TC# 2.A.1.13.10), OATP1C1 controls skeletal muscle regeneration (Mayerl et al. 2018).

Animals

SLCO1C1 of Homo sapiens

 
2.A.60.1.16 solute carrier organic anion transporter family, member 5A1AnimalsSLCO5A1 of Homo sapiens
 
2.A.60.1.17 solute carrier organic anion transporter family, member 6A1AnimalsSLCO6A1 of Homo sapiens
 
2.A.60.1.18 solute carrier organic anion transporter family, member 3A1AnimalsSLCO3A1 of Homo sapiens
 
2.A.60.1.19

Solute carrier organic anion transporter family member 2A1 (Prostaglandin uptake transporter, PGT) (Solute carrier family 21 member 2). Transports prostaglandin E2 and plays a role in F4 mediated neonatal diarrhoea. (Schuster 2002; Ohkura et al. 2014).

Animals

SLCO2A1 of Homo sapiens

 
2.A.60.1.2

Prostaglandin transporter, Pgt or PGT (SLC21A2) (substrates: eicosanoids including several prostaglandins and thromboxanes). Prostaglandins (PGs) transported include PGE2 PGF and PGH2 (Chi and Schuster, 2010).  Pgt is an important mediator of ovulation, and its inhibitors are potential candidates for nonhormonal contraception (Yerushalmi et al. 2016). PGT is involved in the clearance of PGE2 from the brain during the recovery phase of LPS-induced acute-phase responses (Hosotani et al. 2015).

Animals

Pgt of Rattus norvegicus

 
2.A.60.1.20

Solute carrier organic anion transporter family member 2B1 (Organic anion transporter B) (OATP-B, OAT2B1, OAT2B1 or OATP2B1) (Organic anion transporter polypeptide-related protein 2) (OATP-RP2) (OATPRP2) (Solute carrier family 21 member 9).  Catalyzes anion exchange in the placenta with cytoplasmic glutamate as the probable exchanging anion (Lofthouse et al. 2015) as well as uptake of ochratoxin (OTA) (Qi et al. 2017).  A trp residue in the middle of TMS11 is essential (Bian et al. 2016). TMSs 1, 2, 4 and 5 seem to form the substrate binding pocket, and TMS 1 is also essential for stability (Fang et al. 2018). The inhibitory effects of the main soy isoflavones (daidzin, daidzein, genistin, genistein, glycitin, glycitein, biochanin A, formononetin) and their metabolites formed in vivo (S-equol, O-desmethylangolensin) towards the human OATP2B1 transporter have been characterized (Navrátilová et al. 2018). Aglycones of soy isoflavones and the main biologically active metabolite S-equol were able to inhibit hOATP2B1-mediated transport with Ki values for most aglycones ranging from 1 to 20 muM (Navrátilová et al. 2018). An interaction between hyperforin and OATP2B1 contributes to hepatocellular and intestinal absorption of its substrates (Schäfer et al. 2019).

Animals

SLCO2B1 (OatP2B1) of Homo sapiens

 
2.A.60.1.21

Oat33Ea of 745 aas with 12 TMSs in a 3 + 3 + 3 + 3 arrangement.

Insects

Oat33Ea of Drosophila melanogaster

 
2.A.60.1.22

Oat homologue of 816 aas

Insects

Oat homologue of Aedes aegypti

 
2.A.60.1.23

Oatp1p1 steroid hormone transporter of 613 aas and 11 TMSs (Popovic et al. 2013).

Animals

Oat1p1 of Danio rerio (Zebrafish) (Brachydanio rerio)

 
2.A.60.1.24

Organic anion transporter, Oatp of 733 (or 724) aas and 12 TMSs (Mulenga et al. 2008).

Oatp of Amblyomma americanum (Lone star tick)

 
2.A.60.1.25

facilitative organic anion carrier, Slco1a6 of 670 aas and 12 TMSs. Also called Kidney-specific organic anion-transporting polypeptide 5 (Oatp5).  Transports bile acids such as taurocholic acid and other anionic compounds (Tian et al. 2015).

Oatp5 of Mus musculus

 
2.A.60.1.26

OATP1C1 of 710 aas and 12 TMSs.  Transports pro-thyroid hormone T4 with high affinity (Nele Bourgeois et al. 2016).

OATP1C1 of Gallus gallus (Chicken)

 
2.A.60.1.27

Drosophila Malpighian tubule transporter, Oatp58Dc, of 789 aas and 12 TMSs (Eraly et al. 2004; Chahine et al. 2012).

Oatp of Drosophila melanogaster (Fruit fly)

 
2.A.60.1.28

Thyroid hormone transporter, OATP1C1, of 710 aas and 12 TMSs in a clear 3 + 3 + 3 + 3 arrangement (Zada et al. 2017).

OATP1C1 of Danio rerio (Zebrafish) (Brachydanio rerio)

 
2.A.60.1.29

LST-3TM12 (LST3; SLCO1B7 is a product of splicing of SLCO1B3 and SLCO1B7, and encodes a protein with 640 aas and 12 TMSs. LST-3TM12 mRNA was verified by polymerase chain reaction showing liver enriched expression (Malagnino et al. 2017). LST-3TM12 is expressed in the PM and ER of hepatocytes and is associated with enhanced cellular accumulation of dehydroepiandrosterone sulfate (Vmax 300 pmol/mg/min; Km 34 µM) and estradiol 17-beta-glucuronide (Vmax 30 µmol/ mg/min; Km 33 µM) (Malagnino et al. 2017).

LST3 of Homo sapiens

 
2.A.60.1.3

Organic anion transporter, Oat3a (SLC21A7) (substrates: thyroid hormones (triiodothyronine and thyroxine) cholate, taurocholate hormones and their conjugates, eicosanoids, other organic anions and cations).  Mediates uptake of ciprofloxacin in mice (Arakawa et al. 2012).

Animals

Oat3a of Rattus norvegicus

 
2.A.60.1.4

Organic anion transporter, OatK1 (SLC21A4) (substrates: bile salts, hormones and their conjugates, eicosanoids, toxins, drugs, methotrexate, zidovudine)

Animals

OatK1 of Rattus norvegicus

 
2.A.60.1.5

Organic anion transporter, OATP2, OAT1B1, SLCO1B1 or OATP1B1 (LST-1) (SLC21A6) (substrates: mono- and bis-glucuronosyl bilirubin, sulfobromophthalein, taurocholate (Km = 14 μM), estrone sulfate, dehydroepiandrosterone sulfate, estradiol-17 β-D-glucuronide and other conjugated steroids (i.e., estrone 3-sulfate), leukotriene C4, eicosanoids (i.e., prostaglandin E2, thromboxane B2, leucotriene C4 and leucotriene E4), thyroid hormones (i.e., thyroxine and triiodothyronine), other organic anions, drugs, β-lactam antibiotics, ochratoxin, xenobiotics, ouabain, valsartan and pravastatin). OatP-C/1B1(SLC21A) (Hogg et al. 2015; Qi et al. 2017). The bile acid (cholic acid) uptake transporter, OatP-C (transports cholic acid without symport with GSH) (Briz et al., 2006; Degorter et al., 2012). Amino acids in TMS2 essential for estrone-3-sulfate transport have been identified (Li et al., 2012).  OATP1B1 exhibits polymorphism related to neonatal hyperbilirubinemia (Zhang et al. 2010).  Tyr258 and Trp259 in TMS6 play different roles in substrate specificity (Huang et al. 2013).  Cyclic ABP aromatic ring substituents like the chloro-phenyl-thio groups increase their ability to inhibit OATP-mediated transport (Herfindal et al. 2014).  TMS11 influences substrate binding, stability and trafficking (Hong et al. 2015).  Transports danoprevir (hepatitis C virus protease inhibitor) (Brennan et al. 2015).  Residues have been identified that are involved in modulating transport kinetics, and this participation strongly depends on the substrate used in the assay (Gruetz et al. 2016). A 336A mutant is detained in the Golgi apparatus and the Y338A mutant exhibited accelerated protein degradation compared to that of the wild-type, but conservative replacement of Y338 withphenylalanine resulted in recovery of uptake and expression. Thus, the NPXY motif between TMSs 6 and 7 is essential for stable localization of OATP1B1 in the plasma membrane (Wang et al. 2019).

Animals

SLCO1B1 of Homo sapiens

 
2.A.60.1.6

Mouse liver Oatp2 (Slco1a4, Oatp1a4) of 670 aas and 12 TMSs in a 3 + 3 + 3 + 3 + 3 arrangement. Substrates include estrone-3-sulfate, dehydroepiandrosterone sulfate, ouabain, β-lactam antibiotics, BQ-123, digoxin (Km = 5.7 μM), bromosulfophthalein but not taurocholate, rocuronium or deltorphin II. Also transports thyroid hormones. Primary and secondary thyroid hormone transporters have been reviewed (Kinne et al., 2011). It catalyzes transport of substrate drugs with neuroprotective properties across the blook-brain barrier (BBB) (Abdullahi et al. 2017).

Animals

Oatp2 (SLC21A5) of Mus musculus

 
2.A.60.1.7Oat9 (SLC21A9) (transports bile salts, eicosanoids and drugs)AnimalsOat9 of Rattus norvegicus
 
2.A.60.1.8

Oat4 (SLC21A10). Transports bile salts, eicosanoids, urate, hormones and their conjugates, toxins and other anions.  Functions in urate reabsorption across the renal appical membrane (Prestin et al. 2014).

Animals

Oat4 of Rattus norvegicus

 
2.A.60.1.9Oat12 (SLC21A12) (transports bile salts, hormones (T3) and eicosanoids (prostaglandin E2))AnimalsSLCO4A1 of Homo sapiens