Abstract
Purpose. To assess the functional characteristics of human organic anion transporter B (OATP-B) in comparison with those of the known, liver-specific OATP-C.
Methods. OATP-B or -C was expressed in HEK293 cells or Xenopus oocytes, and uptakes of estradiol-17β-glucuronide and estrone-3-sulfate were measured using radiolabeled compounds.
Results. OATP-C transported both estrone-3-sulfate and estradiol-17β-glucuronide, whereas OATP-B transported only the former. OATP-C-mediated uptake of estrone-3-sulfate exhibited biphasic saturation kinetics, whereas transports of estradiol-17β-glucuronide by OATP-C and estrone-3-sulafte by OATP-B followed single-saturation kinetics. Inhibition kinetics showed that only the high-affinity site for estrone-3-sulfate on OATP-C was shared with glucuronide conjugates. Uptake of [3H]estrone-3-sulfate by OATP-B was inhibited by sulfate conjugates but not by glucuronide conjugates, whereas its uptake by OATP-C was inhibited by both types of conjugates.
Conclusions. OATP-B accepted sulfate conjugates of steroids but not glucuronide conjugates, whereas OATP-C transported both types of steroid conjugates. Transport of estrone-3-sulfate by OATP-B and -C followed single- and biphasic-saturation kinetics, respectively, and the high-affinity site on OATP-C was the same as that for estradiol-17β-glucuronide. Other OATPs, OATP-A and OATP-8, reportedly exhibit different preferences for steroid conjugates, and the specific recognition of sulfate conjugates seems to be unique to OATP-B.
Similar content being viewed by others
REFERENCES
M. Müller and P. L. M. Jansen. Molecular aspects of hepatobiliary transport. Am. J. Physiol. 272:G1285-G1303 (1997).
T. Sekine, S.H. Cha, and H. Endou. The multispecific organic anion transporter (OAT) family. Pflügers Arch. 440:337–350 (2000).
H. Yabuuchi, I. Tamai, K. Morita, T. Kouda, K. Miyamoto, E. Takeda, and A. Tsuji. Hepatic sinusoidal membrane transport of anionic drugs mediated by anion transporter Npt1. J. Pharmacol. Exp. Ther. 286:1391–1396 (1998).
H. Uchino, I. Tamai, K. Yamashita, Y. Minemoto, Y. Sai, H. Yabuuchi, K. Miyamoto, E. Takeda, and A. Tsuji. p-Aminohippuric acid transport at renal apical membrane mediated by human inorganic phosphate transporter NPT1. Biochem. Biophys. Res. Commun. 270:254–259 (2000).
E. Jacquemin, B. Hagenbuch, B. Stieger, A. W. Wolkoff, and P. J. Meier. Expression cloning of a rat liver Na+-independent organic anion transporter. Proc. Natl. Acad. Sci. USA 91:133–137 (1994).
A. J. Bergwerk, X. Shi, A. C. Ford, N. Kanai, E. Jacquemin, R. D. Burk, S. Bai, P. M. Novikoff, B. Stieger, P. J. Meier, V. L. Schuster, and A. W. Wolkoff. Immunologic distribution of an organic anion transport protein in rat liver and kidney. Am. J. Physiol. 271:G231-G238 (1996).
R. Lu, N. Kanai, Y. Bao, and V. L. Schuster. Cloning, in vitro expression, and tissue distribution of a human prostaglandin transporter cDNA (hPGT). J. Clin. Invest. 98:1142–1149 (1996).
T. Abe, M. Kakyo, T. Tokui, R. Nakagomi, T. Nishio, D. Nakai, H. Nomura, M. Unno, M. Suzuki, T. Naitoh, S. Matsuo, and H. Yawo. Identification of a novel gene family encoding human liver-specific organic anion transporter LST-1. J. Biol. Chem. 274:17159–17163 (1999).
G. A. Kullak-Ublick, B. Hagenbush, B. Stieger, C. D. Schteingart, A. F. Hoffman, A. W. Wolkoff, and P. J. Meier. Molecular and functional characterization of an organic anion transporting polypeptide cloned from human liver. Gastroenterology 109:1274–1282 (1995).
J. Konig, Y. Cui, A. T. Nies, and D. Keppler. Localization and genomic organization of a new hepatocellular organic anion transporting polypeptide. J. Biol. Chem. 275:23161–23168 (2000).
J, Konig, Y. Cui, A. T. Nies, and D. Keppler. A novel human organic anion transporting polypeptide localized to the basolateral hepatocyte membrane. Am. J. Physiol. 278:G156-G164 (2000).
I. Tamai, J. Nezu, H. Uchino, Y. Sai, A. Oku, M. Shimane, and A. Tsuji. Molecular identification and characterization of novel members of the human organic anion transporter (OATP) family. Biochem. Biophys. Res. Commun. 273:251–260 (2000).
B. Hsiang, Y. Zhu, Z. Wang, Y. Wu, V. Sasseville, W.-P. Yang, and T. G. Kirchgessner. A novel human hepatic organic anion transporting polypeptide (OATP-2). J. Biol. Chem. 274:37161–37168 (1999).
B. Noé, B. Hagenbuch, B. Stieger, and P. J. Meier. Isolation of a multispecific organic anion and cardiac glycoside transporter from rat brain. Proc. Natl. Acad. Sci. USA 94:10346–10350 (1997).
T. Abe, M. Kakyo, H. Sakagami, T. Tokui, T. Nishio, M. Tanemoto, H. Nomura, S. C. Hebert, S. Matsuno, H. Kondo, and H. Yawo. 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 (1998).
V. Cattori, B. Hagenbuch, N. Hagenbuch, B. Stieger, R. Ha, K. E. Winterhalter, and P. J. Meier. Identification of organic anion transporting polypeptide 4 (Oatp4) as a major full-length isoform of the liver-specific transporter-1 (rlst-1) in rat liver. FEBS Lett. 474:242–245 (2000).
T. Nishio, H. Adachi, R. Nakagomi, T. Tokui, E. Sato, M. Tanemoto, K. Fujiwara, M. Okabe, T. Onogawa, T. Suzuki, D. Nakai, K. Shiiba, M. Suzuki, H. Ohtani, Y. Kondo, M. Unno, S. Ito, K. Iinuma, K. Nunoki, S. Matsuno, and T. Abe. Molecular identification of a rat novel organic anion transporter moat1, which transports prostaglandin D(2), leukotriene C(4), and taurocholate. Biochem. Biophys. Res. Commun. 275:831–838 (2000).
P. V. Balimane, I. Tamai, A. Guo, T. akanishi, H. Kitada, F. H. Leibach, A. Tsuji, and P. J. Sinko. Direct evidence for peptide transporter (PepT1)-mediated uptake of a nonpeptide prodrug, valacyclovir. Biochem. Biophys. Res. Commun. 250:246–251 (1998).
M. M. Bradford. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem. 72:248–254 (1976).
Y. Cui, J. Konig, I. Inka, U. Buchholz, and D. Keppler. Hepatic uptake of bilirubin and its conjugates by the human organic anion-transporting poly peptide SLC21A6. J. Biol. Chem. 276:9626–9630 (2001).
T. Iwatsubo, H. Suzuki, N. Shimada, K. Chiba, T. Ishizaki, C. E. Green, C. A. Tyson, T. Yokoi, T. Kamataki, and Y. Sugiyama. Prediction of in vivo hepatic metabolic clearance of YM796 from in vitro data by use of human liver microsome and recombinant P-450 isozymes. J. Pharmacol. Exp. Ther. 282:909–919 (1997).
K. R. Korzekwa, N. Krishnamachary, M. Shou, A. Ogai, R. A. Parise, A. E. Rettie, F. J. Gonzalez, and T. S. Tracy. Evaluation of atypical cytochrome P450 kinetics with two-substrate model: Evidence that multiple substrates can simultaneously bind to cytochrome P450 active sites. Biochemistry 37:4137–4147 (1998).
H. Honjo, J. Kitawaki, M. Itoh, J. Yasuda, K. Iwasaku, M. Urabe, K. Naitoh, T. Yamamoto, H. Okada, T. Ohkubo, and T. Nambara. Serum and urinary estrone sulfate during the menstrual cycle, measured by a direct radioimmunoassay, and fate of exogenously injected estrone sulfate. Hormone Res. 27:61–68 (1987).
T. Hirohashi, H. Suzuki, and Y. Sugiyama. Characterization of the transport properties of cloned rat multidrug resistance-associated protein 3 (MRP3). J. Biol. Chem. 274:15181–15185 (1999).
P. J. Meier, U. Eckhardt, A. Schroeder, B. Hagenbuch, and B. Stieger. Substrate specificity of sinusoidal bile acid and organic anion uptake systems in rat and human liver. Hepatology 26:1667–1677 (1997).
S. H. Cha, T. Sekine, H. Kusuhara, E. Yu, J. Y. Kim, D. K. Kim, Y. Sugiyama, Y. Kanai, and H. Endou. Molecular cloning and characterization of multispecific organic anion transporter 4 expressed in the placenta. J. Biol. Chem. 275:4507–4512 (2000).
G. A. Kullak-Ublick, M. G. Ismair, S B. tieger, L. Landmann, R. Huber, F. Pizzagalli, K. Fattinger, P. J. Meier, and B. Hagenbuch. Organic anion-transporting polypeptide B (OATP-B) and its functional comparison with three other OATPs of human liver. Gastroenterology 120:525–533 (2001).
M. Kakyo, H. Sakagami, T. Nishio, D. Nakai, R. Nakagomi, T. Tokui, T. Naitoh, S. Matsuno, T. Abe, and H. Yawo. Immunohistochemical distribution and functional characterization of an organic anion transporting polypeptide 2 (oatp2). FEBS Lett. 445:343–346 (1999).
H. C. Walters, A. L. Craddock, H. Fusegawa, M. C. Willingham, and P. A. Dawson. Expression, transport properties, and chromosomal location of organic anion transporter subtype 3. Am. J. Physiol. 279:G1188-G1200 (2000).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Tamai, I., Nozawa, T., Koshida, M. et al. Functional Characterization of Human Organic Anion Transporting Polypeptide B (OATP-B) in Comparison with Liver-Specific OATP-C. Pharm Res 18, 1262–1269 (2001). https://doi.org/10.1023/A:1013077609227
Issue Date:
DOI: https://doi.org/10.1023/A:1013077609227