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Gene Review

SLC22A8  -  solute carrier family 22 (organic anion...

Homo sapiens

Synonyms: OAT3, Organic anion transporter 3, Solute carrier family 22 member 8, hOAT3
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Disease relevance of SLC22A8

  • In this study, the mRNA levels of the organic ion transporters were quantified by real-time PCR in normal parts of renal tissues from seven nephrectomized patients with renal cell carcinoma, and the distributions and localization of human (h)OAT1, hOAT3, and hOCT2 proteins were investigated by immunohistochemical analyses in the human kidney [1].
  • CONCLUSIONS: These results suggest that the hOAT3 mRNA level is a significant marker of pharmacokinetics with which to predict the rate of elimination of cefazolin in patients with mesangial proliferative glomerulonephritis [2].

High impact information on SLC22A8

  • Stable isomers of 1-SMP, (2-SMP and 4-SMP) competitively inhibited the uptake of characteristic substrates p-aminohippurate for hOAT1 and estrone sulfate for hOAT3 [3].
  • Transactivation assays revealed that HNF1alpha and HNF1beta markedly increased hOAT3 promoter activity, where the transactivation potency of HNF1beta was lower than that of HNF1alpha [4].
  • It was also demonstrated that the promoter activity of hOAT3 is repressed by DNA methylation [4].
  • This suggests a synergistic action of the HNF1alpha/HNF1alpha homodimer or HNF1alpha/HNF1beta heterodimer and DNA demethylation for the constitutive expression of hOAT3 [4].
  • The minimal promoter of hOAT3 was identified to be located approximately 300 base pairs upstream of the transcriptional start site, where there are canonical TATA and hepatocyte nuclear factor (HNF1) binding motifs, which are conserved in the rodent Oat3 genes [4].

Biological context of SLC22A8


Anatomical context of SLC22A8

  • When human OAT3 (hOAT3) and hOAT4 were expressed in Xenopus laevis oocytes, only hOAT3 showed [3H]cortisol uptake in excess of that of water-injected control oocytes [8].
  • Organic anion transporters, such as Oatp3 and Oat3, play a major role in the uptake of amphipathic and hydrophilic organic anions, respectively, at the brush border surface of the CPE, while the organic cation transporters, Oct2 and/or Oct3, have been suggested to be involved in the uptake of hydrophilic organic cations [9].
  • Immunohistochemical analysis revealed that hOAT1 and hOAT3 are expressed in the cytoplasmic membrane and cytoplasm of human choroid plexus [10].
  • In contrast, OAT3 abundance in both kidney cortex homogenates and in basolateral membranes increased by 3 days after the ligation [11].
  • The purpose of the present study was to elucidate the expression of human organic anion transporter 1 (hOAT1) and hOAT3 in the choroid plexus of the human brain and their interactions with neurotransmitter metabolites using stable cell lines [10].

Associations of SLC22A8 with chemical compounds


Physical interactions of SLC22A8

  • Inhibition potency of probenecid for the uptake of fexofenadine was compared between hOAT3 and organic anion-transporting peptide 1B3 (hOATP1B3), a transporter responsible for the hepatic uptake of fexofenadine (Drug Metab Dispos 33:1477-1481, 2005) [13].
  • The half-maximal inhibitory concentrations of famotidine for [3H]estrone sulfate transport by hOAT3 and [14C]tetraethylammonium transport by hOCT2 (300 microM and 1.8 mM, respectively) were higher than those of cimetidine (53 and 67 microM, respectively) [15].

Other interactions of SLC22A8

  • RESULTS: Among 120 healthy individuals, 5 nonsynonymous variants and 1 nonsynonymous variant were observed in the OATP-C and OAT3 genes, respectively [16].
  • These parameters were comparable with those for hOAT1 and/or hOAT3 [12].
  • The apparent Km values for hOAT2-, hOAT3- and hOAT4-mediated tetracycline uptakes were 439.9 +/- 23.0, 566.2 +/- 28.4 and 122.7 +/- 16.0 microM, respectively [17].
  • The K(i) value of probenecid for hOAT3, but not for hOATP1B3, was significantly lower than the maximum unbound plasma concentration of probenecid at clinical dosages [13].
  • In conclusion, these data indicate that MTX treatment down-regulates expression levels of Mrp2, Oat1 and Oat3, and its effects are recovered by leucovorin [18].

Analytical, diagnostic and therapeutic context of SLC22A8


  1. Gene expression levels and immunolocalization of organic ion transporters in the human kidney. Motohashi, H., Sakurai, Y., Saito, H., Masuda, S., Urakami, Y., Goto, M., Fukatsu, A., Ogawa, O., Inui, K. J. Am. Soc. Nephrol. (2002) [Pubmed]
  2. Pharmacokinetic significance of renal OAT3 (SLC22A8) for anionic drug elimination in patients with mesangial proliferative glomerulonephritis. Sakurai, Y., Motohashi, H., Ogasawara, K., Terada, T., Masuda, S., Katsura, T., Mori, N., Matsuura, M., Doi, T., Fukatsu, A., Inui, K. Pharm. Res. (2005) [Pubmed]
  3. Uptake of Chemically Reactive, DNA-Damaging Sulfuric Acid Esters into Renal Cells by Human Organic Anion Transporters. Bakhiya, N., Stephani, M., Bahn, A., Ugele, B., Seidel, A., Burckhardt, G., Glatt, H. J. Am. Soc. Nephrol. (2006) [Pubmed]
  4. Regulation of the expression of human organic anion transporter 3 by hepatocyte nuclear factor 1alpha/beta and DNA methylation. Kikuchi, R., Kusuhara, H., Hattori, N., Shiota, K., Kim, I., Gonzalez, F.J., Sugiyama, Y. Mol. Pharmacol. (2006) [Pubmed]
  5. The human organic anion transporter 3 (OAT3; SLC22A8): genetic variation and functional genomics. Erdman, A.R., Mangravite, L.M., Urban, T.J., Lagpacan, L.L., Castro, R.A., de la Cruz, M., Chan, W., Huang, C.C., Johns, S.J., Kawamoto, M., Stryke, D., Taylor, T.R., Carlson, E.J., Ferrin, T.E., Brett, C.M., Burchard, E.G., Giacomini, K.M. Am. J. Physiol. Renal Physiol. (2006) [Pubmed]
  6. Torsemide renal clearance and genetic variation in luminal and basolateral organic anion transporters. Vormfelde, S.V., Schirmer, M., Hagos, Y., Toliat, M.R., Engelhardt, S., Meineke, I., Burckhardt, G., Nürnberg, P., Brockmöller, J. British journal of clinical pharmacology. (2006) [Pubmed]
  7. Analyses of 5' regulatory region polymorphisms in human SLC22A6 (OAT1) and SLC22A8 (OAT3). Bhatnagar, V., Xu, G., Hamilton, B.A., Truong, D.M., Eraly, S.A., Wu, W., Nigam, S.K. J. Hum. Genet. (2006) [Pubmed]
  8. Presence of organic anion transporters 3 (OAT3) and 4 (OAT4) in human adrenocortical cells. Asif, A.R., Steffgen, J., Metten, M., Grunewald, R.W., Müller, G.A., Bahn, A., Burckhardt, G., Hagos, Y. Pflugers Arch. (2005) [Pubmed]
  9. Efflux transport systems for organic anions and cations at the blood-CSF barrier. Kusuhara, H., Sugiyama, Y. Adv. Drug Deliv. Rev. (2004) [Pubmed]
  10. Expression of human organic anion transporters in the choroid plexus and their interactions with neurotransmitter metabolites. Alebouyeh, M., Takeda, M., Onozato, M.L., Tojo, A., Noshiro, R., Hasannejad, H., Inatomi, J., Narikawa, S., Huang, X.L., Khamdang, S., Anzai, N., Endou, H. J. Pharmacol. Sci. (2003) [Pubmed]
  11. Renal elimination of p-aminohippurate (PAH) in response to three days of biliary obstruction in the rat. The role of OAT1 and OAT3. Brandoni, A., Anzai, N., Kanai, Y., Endou, H., Torres, A.M. Biochim. Biophys. Acta (2006) [Pubmed]
  12. Characterization of the Uptake of Organic Anion Transporter (OAT) 1 and OAT3 Substrates by Human Kidney Slices. Nozaki, Y., Kusuhara, H., Kondo, T., Hasegawa, M., Shiroyanagi, Y., Nakazawa, H., Okano, T., Sugiyama, Y. J. Pharmacol. Exp. Ther. (2007) [Pubmed]
  13. Inhibition of oat3-mediated renal uptake as a mechanism for drug-drug interaction between fexofenadine and probenecid. Tahara, H., Kusuhara, H., Maeda, K., Koepsell, H., Fuse, E., Sugiyama, Y. Drug Metab. Dispos. (2006) [Pubmed]
  14. Renal Transport of Adefovir, Cidofovir, and Tenofovir by SLC22A Family Members (hOAT1, hOAT3, and hOCT2). Uwai, Y., Ida, H., Tsuji, Y., Katsura, T., Inui, K. Pharm. Res. (2007) [Pubmed]
  15. Different transport properties between famotidine and cimetidine by human renal organic ion transporters (SLC22A). Motohashi, H., Uwai, Y., Hiramoto, K., Okuda, M., Inui, K. Eur. J. Pharmacol. (2004) [Pubmed]
  16. Polymorphisms of OATP-C (SLC21A6) and OAT3 (SLC22A8) genes: consequences for pravastatin pharmacokinetics. Nishizato, Y., Ieiri, I., Suzuki, H., Kimura, M., Kawabata, K., Hirota, T., Takane, H., Irie, S., Kusuhara, H., Urasaki, Y., Urae, A., Higuchi, S., Otsubo, K., Sugiyama, Y. Clin. Pharmacol. Ther. (2003) [Pubmed]
  17. Human organic anion transporters mediate the transport of tetracycline. Babu, E., Takeda, M., Narikawa, S., Kobayashi, Y., Yamamoto, T., Cha, S.H., Sekine, T., Sakthisekaran, D., Endou, H. Jpn. J. Pharmacol. (2002) [Pubmed]
  18. Effect of methotrexate treatment on expression levels of multidrug resistance protein 2, breast cancer resistance protein and organic anion transporters Oat1, Oat2 and Oat3 in rats. Shibayama, Y., Ushinohama, K., Ikeda, R., Yoshikawa, Y., Motoya, T., Takeda, Y., Yamada, K. Cancer Sci. (2006) [Pubmed]
  19. Molecular cloning and characterization of two novel human renal organic anion transporters (hOAT1 and hOAT3). Race, J.E., Grassl, S.M., Williams, W.J., Holtzman, E.J. Biochem. Biophys. Res. Commun. (1999) [Pubmed]
  20. Development of High-specificity Antibodies against Renal Urate Transporters Using Genetic Immunization. Xu, G., Chen, X., Wu, D., Shi, S., Wang, J., Ding, R., Hong, Q., Feng, Z., Lin, S., Lu, Y. J. Biochem. Mol. Biol. (2006) [Pubmed]
  21. Identification and characterization of human organic anion transporter 3 expressing predominantly in the kidney. Cha, S.H., Sekine, T., Fukushima , J.I., Kanai, Y., Kobayashi, Y., Goya, T., Endou, H. Mol. Pharmacol. (2001) [Pubmed]
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