Human Transporters

OAT4New

OAT4

Aliases: None

Gene name: Solute carrier family 22 member 11 (SLC22A11)

Summary

OAT4 is a broad-specificity bidirectional organic anion / dicarboxylate exchanger with endogenous substrates like steroid sulfate conjugates, and xenobiotic substrates including pharmaceutical drugs, phytochemicals, and environmental pollutants. Its cDNA was first isolated from the kidney, and the gene was later also found to be expressed in the placenta, adrenal gland, and salivary gland ducts. The SLC22A11 gene encodes a 550-amino acid, ~70-kDa protein that shares 38 to 44% amino acid sequence identity with other OAT family members. Unlike OAT1 and OAT3 localized to the basolateral membrane of renal proximal tubule cells, OAT4 is positioned apically, and contributes to both the reabsorption and active secretion of its substrates. OAT4 is also a major syncytiotrophoblastic anion transporter involved in the placental uptake of sulfated steroid precursors and other organic anions from the fetal circulation. The current FDA and EMA guidelines contain no recommendations on the in vitro investigation of OAT4 liabilities.

Localization

In the kidney, OAT4 is localized on the apical side of proximal tubule cells [1] [2] [3], facing the tubular lumen, unlike OATs 1-3, all localized basolaterally. The rank order of OAT expression in the kidney is OAT1 >> OAT3 > OAT4 [4]. In the placenta, OAT4 was observed on the basolateral membrane of the syncytiotrophoblastic layer [5]. This was the first organic anion transporter to be identified in the human placenta, where it is expressed abundantly and plays an important role in the uptake of organic anions from the fetus [6]. The expression of OAT4 along with OAT3 was confirmed by RT-PCR in the adrenal cortex as well as the adrenocortical cell line NCI-H295R [7]. OAT4 expression was also verified in the large intestine and the CaCo2 cell line [8], and by immunohistochemistry in the salivary gland ducts [3].

 

Function, physiology, and clinically significant polymorphisms

The SLC22A11 gene encodes a 550-amino acid, ~70-kDa protein with 12 putative membrane-spanning domains. The protein shares 38 to 44% amino acid sequence identity with other OAT family members. OAT4 is a bidirectional organic anion / dicarboxylate exchanger [1], albeit OAT4-mediated unidirectional p-aminohippuric acid efflux was also observed [9].  While most studies have confirmed a sodium-independent mode of operation, Ugele et al. have reported partly sodium-dependent transport of estrogens and their precursors [10]. An important class of OAT4 substrates comprises steroid sulfate conjugates, as opposed to glucuronide conjugates which do not interact with OAT4 either as substrates or inhibitors. OAT4 transports estrone 3-sulfate (E3S) and dehydroepiandrosterone sulfate (DHEAS) with high affinity, and DHEAS competes with E3S on OAT4. The sulfate-conjugated metabolite of 17α-ethinylestradiol, a synthetic estrogen receptor agonist, was shown to be taken up from blood into the proximal tubule cells by OAT3 and secreted into the urine by OAT4 [11]. Sulfate conjugates of the flavonoid quercetin [12] and the isoflavone daidzein [13] are also OAT4 substrates. The chemically unrelated uric acid is a low-affinity substrate of OAT4, although the transport of E3S versus urate by OAT4 involve different mechanisms [9][14][15]. Additionally, OAT4 was found to transport ochratoxin A and, with a low affinity, 6-carboxyfluorescein [6][2][9].

Sulfobromophthalein is a potent inhibitor of OAT4-mediated E3S transport; probenecid, indomethacin, ibuprofen, diclofenac, furosemide, bumetanide, and corticosterone showed modest but dose-dependent inhibition [6][16]. The inhibitory effect of some angiotensin II receptor antagonists and leukotriene receptor antagonists suggests that OAT4 accepts sulfate, carboxylate and tetrazole groups as an anionic motif [16].

In the kidney, OAT4 localized to the luminal side of proximal tubules contributes to both the reabsorption and secretion of endogenous substances and xenobiotics [1][9]. Basolateral OATs and apical OAT4 cooperate in the active secretion of a broad range of substances including antibiotics like cephalosporins and tetracyclines [17][18][19], anticancer drugs like pemetrexed [20], uremic toxins like indoxyl sulfate [21], and dietary plant-derived compounds like the sulfate conjugates of hydroxycinnamic acid [22]. While OAT4 contributes to the urinary secretion of the aforementioned substances, other compounds including uric acid and levocetirizine are reabsorbed but not secreted by OAT4 [14][23].

In the placenta, OAT4 localized to the basolateral side of the syncytiotrophoblastic layer is one of several transporters involved in the transport of endogenous molecules and xenobiotics through the blood-placenta barrier. As such, OAT4 plays a crucial role in the protection of the fetus from exposure to environmental toxicants like perfluorocarboxylates [24][25][26][27]. Besides its protective and nutritive functions, the placenta is also an active site of steroid hormone synthesis and a major source of elevated estrogen levels in maternal blood [5][28]. In humans, OATB2B1 and OAT4 are responsible for the placental uptake of steroid hormone precursors. Sulfate-conjugated precursors required for estrogen synthesis, like the fetal liver-derived 16-hydroxy-DHEAS, are imported into the placenta by OAT4 [29]. OAT4 expression in the syncytiotrophoblast was shown to be regulated by protein kinase A, and bromosulfophthalein inhibited estrogen synthesis by blocking OAT4 [30]. For both OAT4 and OATP2B1, glutamate exchange was identified as the dominant driving force for organic anion uptake from the fetal circulation [31].

The expression of OAT4, along with OAT3, was confirmed in the adrenal cortex; its functional significance is, however, unclear as OAT3 but not OAT4 was shown to be involved in cortisol secretion [7].

Although naturally occurring exonic variants of OAT4 have no known association with disease, three rare SNPs (L29P, R48Stop, H469R) were demonstrated to display complete loss of function, and common nonsynonymous variants displayed reduced E3S transport. Null mutations caused loss of protein expression and/or plasma membrane localization [32]. The intronic polymorphism rs17300741 showed weak association with renal underexcretion type gout [33].

 

Clinical relevance

Many clinical drugs and toxins interact with OAT4 as substrates, inhibitors, or both. OAT4 was shown to be a target of lesinurad, a selective uric acid reabsorption inhibitor used in combination with xanthine oxidase inhibitors to treat hyperuricemia. Since lesinurad selectively inhibits the apically localized urate transporters URAT1 and OAT4, it has a favorable safety profile in the treatment of gout [34][35]. The anti-inflammatory drug tranilast also potently reduces serum uric acid levels and causes uricosuria by inhibiting renal urate transporters including OAT4 [36].

For the cephalosporin antibiotic cephaloridine, OAT4-mediated efflux seems to be the limiting step in clearance, and the accumulation of cephaloridine in proximal tubule cells may cause nephrotoxicity [18][19]. Similarly, the nephrotoxic phytochemical aristolochic acid can accumulate and cause damage in proximal tubule cells because the affinity of OAT4 to these toxins is 40-fold lower compared to OAT1 and OAT3 [37].

Although angiotensin II receptor blockers inhibited OAT4-mediated E3S uptake in vitro, this was of no clinical relevance as IC50 values were higher than the therapeutic plasma concentration [14]. On the other hand, some angiotensin II inhibitors are also substrates of OAT4, and OAT4 may contribute to the fetotoxic effect of olmesartan by mediating its transplacental transport [38]. 

 

Regulatory requirements

The current FDA and EMA guidelines contain no recommendations on the in vitro investigation of OAT4 liabilities.

Table: Summary information for OAT4

Location

Endogenous substrate

In vitro substrates used experimentally

Substrate drugs

Inhibitors

placenta, kidney

DHEAS, E3S, uric acid

DHEAS, E3S, ochratoxin A

olmesartan

tetracycline, bromosulfophthalein

 

References

 

[1]        S. Ekaratanawong et al., “Human Organic Anion Transporter 4 Is a Renal Apical Organic Anion/Dicarboxylate Exchanger in the Proximal Tubules,” J. Pharmacol. Sci., vol. 94, no. 3, pp. 297–304, 2004, doi: 10.1254/jphs.94.297.

[2]        E. Babu et al., “Role of human organic anion transporter 4 in the transport of ochratoxin A,” Biochim. Biophys. Acta - Mol. Cell Res., vol. 1590, no. 1–3, pp. 64–75, Jun. 2002, doi: 10.1016/S0167-4889(02)00187-8.

[3]        R. Ikarashi, K. Shibasaki, and A. Yamaguchi, “Immunohistochemical studies of organic anion transporters and urate transporter 1 expression in human salivary gland,” Acta Odontol. Scand., vol. 71, no. 2, pp. 312–316, Mar. 2013, doi: 10.3109/00016357.2012.680904.

[4]        C. Hilgendorf, G. Ahlin, A. Seithel, P. Artursson, A. Ungell, and J. Karlsson, “Expression of Thirty-six Drug Transporter Genes in Human Intestine , Liver , Kidney , and Organotypic Cell Lines ABSTRACT :,” DMD, vol. 35, no. 8, pp. 1333–1340, 2007, doi: 10.1124/dmd.107.014902.ularly.

[5]        B. Ugele, M. V. St-Pierre, M. Pihusch, A. Bahn, and P. Hantschmann, “Characterization and identification of steroid sulfate transporters of human placenta,” Am. J. Physiol. Metab., vol. 284, no. 2, pp. E390–E398, Feb. 2003, doi: 10.1152/ajpendo.00257.2002.

[6]        S. H. Cha et al., “Molecular Cloning and Characterization of Multispecific Organic Anion Transporter 4 Expressed in the Placenta,” J. Biol. Chem., vol. 275, no. 6, pp. 4507–4512, Feb. 2000, doi: 10.1074/jbc.275.6.4507.

[7]        A. R. Asif et al., “Presence of organic anion transporters 3 (OAT3) and 4 (OAT4) in human adrenocortical cells,” Pflügers Arch. - Eur. J. Physiol., vol. 450, no. 2, pp. 88–95, May 2005, doi: 10.1007/s00424-004-1373-3.

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[9]        Y. Hagos, D. Stein, B. Ugele, G. Burckhardt, and A. Bahn, “Human Renal Organic Anion Transporter 4 Operates as an Asymmetric Urate Transporter,” J. Am. Soc. Nephrol., vol. 18, no. 2, pp. 430–439, Feb. 2007, doi: 10.1681/ASN.2006040415.

[10]      B. Ugele, A. Bahn, and M. Rex-Haffner, “Functional differences in steroid sulfate uptake of organic anion transporter 4 (OAT4) and organic anion transporting polypeptide 2B1 (OATP2B1) in human placenta,” J. Steroid Biochem. Mol. Biol., vol. 111, no. 1–2, pp. 1–6, Jul. 2008, doi: 10.1016/j.jsbmb.2008.04.001.

[11]      Y.-H. Han, D. Busler, Y. Hong, Y. Tian, C. Chen, and A. D. Rodrigues, “Transporter Studies with the 3- O -Sulfate Conjugate of 17α-Ethinylestradiol: Assessment of Human Kidney Drug Transporters,” Drug Metab. Dispos., vol. 38, no. 7, pp. 1064–1071, Jul. 2010, doi: 10.1124/dmd.109.031526.

[12]      C. C. Wong, Y. Akiyama, T. Abe, J. D. Lippiat, C. Orfila, and G. Williamson, “Carrier-mediated transport of quercetin conjugates: Involvement of organic anion transporters and organic anion transporting polypeptides,” Biochem. Pharmacol., vol. 84, no. 4, pp. 564–570, Aug. 2012, doi: 10.1016/j.bcp.2012.05.011.

[13]      G. Grosser, B. Döring, B. Ugele, J. Geyer, S. E. Kulling, and S. T. Soukup, “Transport of the soy isoflavone daidzein and its conjugative metabolites by the carriers SOAT, NTCP, OAT4, and OATP2B1,” Arch. Toxicol., vol. 89, no. 12, pp. 2253–2263, Dec. 2015, doi: 10.1007/s00204-014-1379-3.

[14]      M. Sato et al., “Involvement of Uric Acid Transporters in Alteration of Serum Uric Acid Level by Angiotensin II Receptor Blockers,” Pharm. Res., vol. 25, no. 3, pp. 639–646, Mar. 2008, doi: 10.1007/s11095-007-9401-6.

[15]      P. Skwara, E. Schömig, and D. Gründemann, “A novel mode of operation of SLC22A11: Membrane insertion of estrone sulfate versus translocation of uric acid and glutamate,” Biochem. Pharmacol., vol. 128, pp. 74–82, Mar. 2017, doi: 10.1016/j.bcp.2016.12.020.

[16]      F. Yamashita et al., “Inhibitory effects of angiotensin II receptor antagonists and leukotriene receptor antagonists on the transport of human organic anion transporter 4,” J. Pharm. Pharmacol., vol. 58, no. 11, pp. 1499–1505, Nov. 2006, doi: 10.1211/jpp.58.11.0011.

[17]      E. Babu et al., “Human Organic Anion Transporters Mediate the Transport of Tetracycline,” Jpn. J. Pharmacol., vol. 88, no. 1, pp. 69–76, 2002, doi: 10.1254/jjp.88.69.

[18]      M. Takeda, E. Babu, S. Narikawa, and H. Endou, “Interaction of human organic anion transporters with various cephalosporin antibiotics,” Eur. J. Pharmacol., vol. 438, no. 3, pp. 137–142, Mar. 2002, doi: 10.1016/S0014-2999(02)01306-7.

[19]      S. Khamdang et al., “Interaction of human and rat organic anion transporter 2 with various cephalosporin antibiotics,” Eur. J. Pharmacol., vol. 465, no. 1–2, pp. 1–7, Mar. 2003, doi: 10.1016/S0014-2999(03)01381-5.

[20]      M. M. Posada et al., “Prediction of Renal Transporter Mediated Drug-Drug Interactions for Pemetrexed Using Physiologically Based Pharmacokinetic Modeling,” Drug Metab. Dispos., vol. 43, no. 3, pp. 325–334, Mar. 2015, doi: 10.1124/dmd.114.059618.

[21]      A. Enomoto et al., “Interactions of human organic anion as well as cation transporters with indoxyl sulfate,” Eur. J. Pharmacol., vol. 466, no. 1–2, pp. 13–20, Apr. 2003, doi: 10.1016/S0014-2999(03)01530-9.

[22]      C. C. Wong, D. Barron, C. Orfila, F. Dionisi, P. Krajcsi, and G. Williamson, “Interaction of hydroxycinnamic acids and their conjugates with organic anion transporters and ATP-binding cassette transporters,” Mol. Nutr. Food Res., vol. 55, no. 7, pp. 979–988, Jul. 2011, doi: 10.1002/mnfr.201000652.

[23]      M. Strolin Benedetti, R. Whomsley, F.-X. Mathy, P. Jacques, P. Espie, and M. Canning, “Stereoselective renal tubular secretion of levocetirizine and dextrocetirizine, the two enantiomers of the H 1 -antihistamine cetirizine,” Fundam. Clin. Pharmacol., vol. 22, no. 1, pp. 19–23, Feb. 2008, doi: 10.1111/j.1472-8206.2007.00543.x.

[24]      C. Yang, K. P. Glover, and X. Han, “Characterization of Cellular Uptake of Perfluorooctanoate via Organic Anion-Transporting Polypeptide 1A2, Organic Anion Transporter 4, and Urate Transporter 1 for Their Potential Roles in Mediating Human Renal Reabsorption of Perfluorocarboxylates,” Toxicol. Sci., vol. 117, no. 2, pp. 294–302, Oct. 2010, doi: 10.1093/toxsci/kfq219.

[25]      O. Midasch, H. Drexler, N. Hart, M. W. Beckmann, and J. Angerer, “Transplacental exposure of neonates to perfluorooctanesulfonate and perfluorooctanoate: a pilot study,” Int. Arch. Occup. Environ. Health, vol. 80, no. 7, pp. 643–648, May 2007, doi: 10.1007/s00420-006-0165-9.

[26]      R. Monroy et al., “Serum levels of perfluoroalkyl compounds in human maternal and umbilical cord blood samples,” Environ. Res., vol. 108, no. 1, pp. 56–62, Sep. 2008, doi: 10.1016/j.envres.2008.06.001.

[27]      M. Kummu et al., “Organic anion transporter 4 (OAT 4) modifies placental transfer of perfluorinated alkyl acids PFOS and PFOA in human placental ex vivo perfusion system,” Placenta, vol. 36, no. 10, pp. 1185–1191, Oct. 2015, doi: 10.1016/j.placenta.2015.07.119.

[28]      W. Chatuphonprasert, K. Jarukamjorn, and I. Ellinger, “Physiology and Pathophysiology of Steroid Biosynthesis, Transport and Metabolism in the Human Placenta,” Front. Pharmacol., vol. 9, no. September, pp. 1–29, Sep. 2018, doi: 10.3389/fphar.2018.01027.

[29]      M. Tomi et al., “Role of OAT4 in Uptake of Estriol Precursor 16α-Hydroxydehydroepiandrosterone Sulfate Into Human Placental Syncytiotrophoblasts From Fetus,” Endocrinology, vol. 156, no. 7, pp. 2704–2712, Jul. 2015, doi: 10.1210/en.2015-1130.

[30]      M. Tomi, Y. Miyata, S. Noguchi, S. Nishimura, T. Nishimura, and E. Nakashima, “Role of protein kinase A in regulating steroid sulfate uptake for estrogen production in human placental choriocarcinoma cells,” Placenta, vol. 35, no. 8, pp. 658–660, Aug. 2014, doi: 10.1016/j.placenta.2014.06.003.

[31]      E. M. Lofthouse et al., “Glutamate cycling may drive organic anion transport on the basal membrane of human placental syncytiotrophoblast,” J. Physiol., vol. 593, no. 20, pp. 4549–4559, Oct. 2015, doi: 10.1113/JP270743.

[32]      J. E. Shima et al., “Genetic variants of human organic anion transporter 4 demonstrate altered transport of endogenous substrates,” Am. J. Physiol. Physiol., vol. 299, no. 4, pp. F767–F775, Oct. 2010, doi: 10.1152/ajprenal.00312.2010.

[33]      M. Sakiyama et al., “A Common Variant of Organic Anion Transporter 4 (OAT4/SLC22A11) Gene Is Associated with Renal Underexcretion Type Gout,” Drug Metab. Pharmacokinet., vol. 29, no. 2, pp. 208–210, 2014, doi: 10.2133/dmpk.DMPK-13-NT-070.

[34]      J. N. Miner et al., “Lesinurad, a novel, oral compound for gout, acts to decrease serum uric acid through inhibition of urate transporters in the kidney,” Arthritis Res. Ther., vol. 18, no. 1, p. 214, Dec. 2016, doi: 10.1186/s13075-016-1107-x.

[35]      C. Yang et al., “Characterization of Stereoselective Metabolism, Inhibitory Effect on Uric Acid Uptake Transporters, and Pharmacokinetics of Lesinurad Atropisomers,” Drug Metab. Dispos., vol. 47, no. 2, pp. 104–113, Feb. 2019, doi: 10.1124/dmd.118.080549.

[36]      A. K. Mandal, A. Mercado, A. Foster, K. Zandi-Nejad, and D. B. Mount, “Uricosuric targets of tranilast,” Pharmacol. Res. Perspect., vol. 5, no. 2, p. e00291, Apr. 2017, doi: 10.1002/prp2.291.

[37]      N. Bakhiya, V. M. Arlt, A. Bahn, G. Burckhardt, D. H. Phillips, and H. Glatt, “Molecular evidence for an involvement of organic anion transporters (OATs) in aristolochic acid nephropathy,” Toxicology, vol. 264, no. 1–2, pp. 74–79, Oct. 2009, doi: 10.1016/j.tox.2009.07.014.

[38]      S. Noguchi, T. Nishimura, A. Fujibayashi, T. Maruyama, M. Tomi, and E. Nakashima, “Organic Anion Transporter 4-Mediated Transport of Olmesartan at Basal Plasma Membrane of Human Placental Barrier,” J. Pharm. Sci., vol. 104, no. 9, pp. 3128–3135, Sep. 2015, doi: 10.1002/jps.24434.

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