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SLCO1B3  -  solute carrier organic anion transporter...

Homo sapiens

 
 
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Disease relevance of SLCO1B3

 

High impact information on SLCO1B3

  • BACKGROUND & AIMS: OATP8 (gene symbol: SLC21A8) is a multispecific uptake system for organic anions, xenobiotics, and peptides expressed at the basolateral (sinusoidal) membrane of human hepatocytes [4].
  • Targeted mutagenesis of the IR-1 element abolished inducibility of the OATP8 promoter by CDCA, confirming its role as a bile acid response element [4].
  • CDCA treatment increased OATP8 messenger RNA levels in human hepatoma cells, suggesting a physiologic role for FXR-mediated OATP8 gene regulation [4].
  • CONCLUSIONS: OATP8 gene expression is regulated by bile acids via FXR/BAR [4].
  • OATP8 expression in cells was quantitated by real-time polymerase chain reaction [4].
 

Biological context of SLCO1B3

  • Mutations in the SLCO1B3 gene affecting the substrate specificity of the hepatocellular uptake transporter OATP1B3 (OATP8) [5].
  • The studied SNPs in SLCO1B3 appear to play a limited role in the disposition of paclitaxel, although their clinical significance in other ethnic populations remains to be investigated [6].
  • Variants in the SLCO1B3 gene: interethnic distribution and association with paclitaxel pharmacokinetics [6].
  • Transport studies and gene expression analyses indicated that B22956 ion is a good substrate to the liver-specific OATP1B3, reported to be poorly expressed or absent in human liver tumors [7].
  • Both latter amino acid substitutions abolished the transport of bile acids mediated by OATP1B3, whereas other substrates, like bromosulfophthalein, were transported by all polymorphic variants of the protein [5].
 

Anatomical context of SLCO1B3

 

Associations of SLCO1B3 with chemical compounds

  • LST-2 transports methotrexate in a saturable and dose-dependent manner [1].
  • Organic anions transported by human OATP8 included sulfobromophthalein, with a K(m) of 3.3 microm, and 17beta-glucuronosyl estradiol, with a K(m) of 5.4 microm [12].
  • In comparison to the high-affinity transport by OATP2, OATP8 transported [(3)H]sulfobromophthalein and [(3)H]monoglucuronosyl bilirubin with lower affinity, with K(m) values of 3.3 and 0.5 microm, respectively [13].
  • An antibody raised against the carboxyl terminus localized OATP8 to the basolateral membrane of human hepatocytes and the recombinant glycoprotein, expressed in MDCKII cells, to the lateral membrane [12].
  • Applying this method to pitavastatin, the observed uptake clearance in human hepatocytes could be almost completely accounted for by OATP2 and OATP8, and about 90% of the total hepatic clearance could be accounted for by OATP2 [14].
 

Physical interactions of SLCO1B3

  • 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) [15].
 

Regulatory relationships of SLCO1B3

  • In transfected Huh7 cells, OATP8 promoter activity was inhibited by 70% when HNF3beta was cotransfected [16].
 

Other interactions of SLCO1B3

  • The corresponding K(i) values were 17 micromol/L for OATP-C, 5 micromol/L for OATP8, and 51 micromol/L for OATP-A [17].
  • Expression of the liver-enriched transcription factor hepatocyte nuclear factor 3beta (HNF3beta) was increased in 70% of HCC and correlated inversely with OATP8 mRNA (r=-0.75, P<0.05) and protein [16].
  • For this, Madin Darby canine kidney strain II (MDCKII) cells stably expressing human OATP1B3, OATP2B1, or OATP1B1, were assayed for the uptake of 3H-labeled O-methyl-dehydroxymethyl-alpha-amanitin [18].
  • PB also decreased MRP6 expression, whereas mRNA levels of OCT1 and OATP8 were down-regulated by RIF and OPZ, respectively [19].
  • These results suggest that OATP1B1 and OATP1B3 as the uptake transporters and MRP2 as the efflux transporter are responsible for the efficient hepatobiliary transport of valsartan [20].
 

Analytical, diagnostic and therapeutic context of SLCO1B3

References

  1. LST-2, a human liver-specific organic anion transporter, determines methotrexate sensitivity in gastrointestinal cancers. Abe, T., Unno, M., Onogawa, T., Tokui, T., Kondo, T.N., Nakagomi, R., Adachi, H., Fujiwara, K., Okabe, M., Suzuki, T., Nunoki, K., Sato, E., Kakyo, M., Nishio, T., Sugita, J., Asano, N., Tanemoto, M., Seki, M., Date, F., Ono, K., Kondo, Y., Shiiba, K., Suzuki, M., Ohtani, H., Shimosegawa, T., Iinuma, K., Nagura, H., Ito, S., Matsuno, S. Gastroenterology (2001) [Pubmed]
  2. Detection of the human organic anion transporters SLC21A6 (OATP2) and SLC21A8 (OATP8) in liver and hepatocellular carcinoma. Cui, Y., König, J., Nies, A.T., Pfannschmidt, M., Hergt, M., Franke, W.W., Alt, W., Moll, R., Keppler, D. Lab. Invest. (2003) [Pubmed]
  3. Sensitivity of bile acid transport by organic anion-transporting polypeptides to intracellular pH. Marin, J.J., Mangas, D., Martinez-Diez, M.C., El-Mir, M.Y., Briz, O., Serrano, M.A. Biochim. Biophys. Acta (2003) [Pubmed]
  4. Human organic anion transporting polypeptide 8 promoter is transactivated by the farnesoid X receptor/bile acid receptor. Jung, D., Podvinec, M., Meyer, U.A., Mangelsdorf, D.J., Fried, M., Meier, P.J., Kullak-Ublick, G.A. Gastroenterology (2002) [Pubmed]
  5. Mutations in the SLCO1B3 gene affecting the substrate specificity of the hepatocellular uptake transporter OATP1B3 (OATP8). Letschert, K., Keppler, D., König, J. Pharmacogenetics (2004) [Pubmed]
  6. Variants in the SLCO1B3 gene: interethnic distribution and association with paclitaxel pharmacokinetics. Smith, N.F., Marsh, S., Scott-Horton, T.J., Hamada, A., Mielke, S., Mross, K., Figg, W.D., Verweij, J., McLeod, H.L., Sparreboom, A. Clin. Pharmacol. Ther. (2007) [Pubmed]
  7. Molecular determinants in the transport of a bile Acid-derived diagnostic agent in tumoral and nontumoral cell lines of human liver. Libra, A., Fernetti, C., Lorusso, V., Visigalli, M., Anelli, P.L., Staud, F., Tiribelli, C., Pascolo, L. J. Pharmacol. Exp. Ther. (2006) [Pubmed]
  8. Identification of phalloidin uptake systems of rat and human liver. Meier-Abt, F., Faulstich, H., Hagenbuch, B. Biochim. Biophys. Acta (2004) [Pubmed]
  9. Identification of OATP1B3 as a high-affinity hepatocellular transporter of paclitaxel. Smith, N.F., Acharya, M.R., Desai, N., Figg, W.D., Sparreboom, A. Cancer Biol. Ther. (2005) [Pubmed]
  10. Transport of fluorescent chenodeoxycholic acid via the human organic anion transporters OATP1B1 and OATP1B3. Yamaguchi, H., Okada, M., Akitaya, S., Ohara, H., Mikkaichi, T., Ishikawa, H., Sato, M., Matsuura, M., Saga, T., Unno, M., Abe, T., Mano, N., Hishinuma, T., Goto, J. J. Lipid Res. (2006) [Pubmed]
  11. Human organic anion transporting polypeptide-C (SLC21A6) is a major determinant of rifampin-mediated pregnane X receptor activation. Tirona, R.G., Leake, B.F., Wolkoff, A.W., Kim, R.B. J. Pharmacol. Exp. Ther. (2003) [Pubmed]
  12. Localization and genomic organization of a new hepatocellular organic anion transporting polypeptide. König, J., Cui, Y., Nies, A.T., Keppler, D. J. Biol. Chem. (2000) [Pubmed]
  13. Hepatic uptake of bilirubin and its conjugates by the human organic anion transporter SLC21A6. Cui, Y., König, J., Leier, I., Buchholz, U., Keppler, D. J. Biol. Chem. (2001) [Pubmed]
  14. Contribution of OATP2 (OATP1B1) and OATP8 (OATP1B3) to the hepatic uptake of pitavastatin in humans. Hirano, M., Maeda, K., Shitara, Y., Sugiyama, Y. J. Pharmacol. Exp. Ther. (2004) [Pubmed]
  15. 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]
  16. The human organic anion transporting polypeptide 8 (SLCO1B3) gene is transcriptionally repressed by hepatocyte nuclear factor 3beta in hepatocellular carcinoma. Vavricka, S.R., Jung, D., Fried, M., Grützner, U., Meier, P.J., Kullak-Ublick, G.A. J. Hepatol. (2004) [Pubmed]
  17. Interactions of rifamycin SV and rifampicin with organic anion uptake systems of human liver. Vavricka, S.R., Van Montfoort, J., Ha, H.R., Meier, P.J., Fattinger, K. Hepatology (2002) [Pubmed]
  18. Molecular characterization and inhibition of amanitin uptake into human hepatocytes. Letschert, K., Faulstich, H., Keller, D., Keppler, D. Toxicol. Sci. (2006) [Pubmed]
  19. Differential regulation of sinusoidal and canalicular hepatic drug transporter expression by xenobiotics activating drug-sensing receptors in primary human hepatocytes. Jigorel, E., Le Vee, M., Boursier-Neyret, C., Parmentier, Y., Fardel, O. Drug Metab. Dispos. (2006) [Pubmed]
  20. Involvement of transporters in the hepatic uptake and biliary excretion of valsartan, a selective antagonist of the angiotensin II AT1-receptor, in humans. Yamashiro, W., Maeda, K., Hirouchi, M., Adachi, Y., Hu, Z., Sugiyama, Y. Drug Metab. Dispos. (2006) [Pubmed]
  21. Drug-drug interaction between pitavastatin and various drugs via OATP1B1. Hirano, M., Maeda, K., Shitara, Y., Sugiyama, Y. Drug Metab. Dispos. (2006) [Pubmed]
 
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