Polymorphisms in OATP-C
The human organic anion transporting polypeptide-C (OATP-C) (gene SLC21A6) is a liver-specific transporter importantly involved in the hepatocellular uptake of a variety of endogenous and foreign chemicals. In this study, we demonstrate the presence of multiple functionally relevant single-nucleotide polymorphisms (SNPs) in OATP-C in a population of African- and European-Americans. Moreover, examination of 14 nonsynonymous polymorphisms indicated that genotypic frequencies were dependent on race. Functional assessment of 16OATP-C alleles in vitro revealed that several variants exhibited markedly reduced uptake of the OATP-C substrates estrone sulfate and estradiol 17β-d-glucuronide. Specifically, alterations in transport were associated with SNPs that introduce amino acid changes within the transmembrane-spanning domains (T217C (Phe-73 → Leu), T245C (Val-82 → Ala), T521C (Val-174 → Ala), and T1058C (Ile-353 → Thr)) and also with those that modify extracellular loop 5 (A1294G (Asn-432 → Asp), A1385G (Asp-462 → Gly), and A1463C (Gly-488 → Ala)). Cell surface biotinylation experiments indicated that the altered transport activity of some OATP-C variants was due, in part, to decreased plasma membrane expression. Given the relatively high genotypic frequency of the T521C (14%) transition in European-Americans and the G1463C (9%) transversion in African-Americans, SNPs in OATP-C may represent a heretofore unrecognized factor influencing drug disposition. The human organic anion transporting polypeptide-C (OATP-C) (gene SLC21A6) is a liver-specific transporter importantly involved in the hepatocellular uptake of a variety of endogenous and foreign chemicals. In this study, we demonstrate the presence of multiple functionally relevant single-nucleotide polymorphisms (SNPs) in OATP-C in a population of African- and European-Americans. Moreover, examination of 14 nonsynonymous polymorphisms indicated that genotypic frequencies were dependent on race. Functional assessment of 16OATP-C alleles in vitro revealed that several variants exhibited markedly reduced uptake of the OATP-C substrates estrone sulfate and estradiol 17β-d-glucuronide. Specifically, alterations in transport were associated with SNPs that introduce amino acid changes within the transmembrane-spanning domains (T217C (Phe-73 → Leu), T245C (Val-82 → Ala), T521C (Val-174 → Ala), and T1058C (Ile-353 → Thr)) and also with those that modify extracellular loop 5 (A1294G (Asn-432 → Asp), A1385G (Asp-462 → Gly), and A1463C (Gly-488 → Ala)). Cell surface biotinylation experiments indicated that the altered transport activity of some OATP-C variants was due, in part, to decreased plasma membrane expression. Given the relatively high genotypic frequency of the T521C (14%) transition in European-Americans and the G1463C (9%) transversion in African-Americans, SNPs in OATP-C may represent a heretofore unrecognized factor influencing drug disposition. single-nucleotide polymorphism organic anion transporting polypeptide single-strand conformational polymorphism polymerase chain reaction restriction fragment length polymorphism cytochrome P450 Variations in the genes encoding drug metabolizing enzymes have long been recognized as important determinants of drug disposition and response. Indeed, certain single-nucleotide polymorphisms (SNPs)1 in cytochrome P450 (CYP) enzymes, such as CYP2C9, CYP2C19, and CYP2D6, are well known determinants of altered drug responsiveness and are often associated with drug toxicity or, in some cases, loss of therapeutic efficacy (1Evans W.E. Relling M.V. Science. 1999; 286: 487-491Crossref PubMed Scopus (2163) Google Scholar,2Meyer U.A. Zanger U.M. Annu. Rev. Pharmacol. Toxicol. 1997; 37: 269-296Crossref PubMed Scopus (496) Google Scholar). More recently, there has been an increasing appreciation of the role of drug transporters in drug disposition. For example, the product of the MDR1 gene, P-glycoprotein, is an efflux transporter involved in the oral drug absorption, distribution to certain tissues, and biliary and urinary excretion of many drugs. Moreover, P-glycoprotein has been shown to have broad and overlapping substrate specificities to CYP enzymes (3Kim R.B. Wandel C. Leake B. Cvetkovic M. Fromm M.F. Dempsey P.J. Roden M.M. Belas F. Chaudhary A.K. Roden D. Wood A.J.J. Wilkinson G.R. Pharm. Res. (N. Y.). 1999; 16: 408-414Crossref PubMed Google Scholar). Furthermore, polymorphisms in theMDR1 gene have been associated with alterations in digoxin (4Hoffmeyer S. Burk O. von Richter O. Arnold H.P. Brockmoller J. Johne A. Cascorbi I. Gerloff T. Roots I. Eichelbaum M. Brinkmann U. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 3473-3478Crossref PubMed Scopus (2384) Google Scholar) and fexofenadine (5Kim R.B. Leake B.F. Choo E.F. Dresser G.K. Kubba S.V. Schwarz U.I. Taylor A. Xie H.-G. McKinsey J. Zhou S. Lu-Bin L. Schuetz J.D. Schuetz E.G. Wilkinson G.R. Clin. Pharmacol. Ther. 2001; 70: 189-199Crossref PubMed Scopus (961) Google Scholar) disposition. Removal of drugs/solutes from the portal circulation involves uptake into hepatocytes as the obligatory first step. Whereas passive diffusion can be involved in the uptake of many uncharged or lipophilic compounds, carrier-mediated processes are often critical for the efficient hepatic uptake of solutes and many drugs. Among the transporters expressed at the basolateral membrane of hepatocytes, members of the organic anion transporting polypeptide (OATP) family (6Jacquemin E. Hagenbuch B. Stieger B. Wolkoff A.W. Meier P.J. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 133-137Crossref PubMed Scopus (552) Google Scholar) have been shown capable of mediating the hepatic uptake of a variety of structurally divergent compounds (7Meier P.J. Eckhardt U. Schroeder A. Hagenbuch B. Stieger B. Hepatology. 1997; 26: 1667-1677Crossref PubMed Scopus (326) Google Scholar). Within this family, OATP-B (8Tamai I. Nezu J. Uchino H. Sai Y. Oku A. Shimane M. Tsuji A. Biochem. Biophys. Res. Commun. 2000; 273: 251-260Crossref PubMed Scopus (557) Google Scholar,9Kullak-Ublick G.A. Ismair M.G. Stieger B. Landmann L. Huber R. Pizzagalli F. Fattinger K. Meier P.J. Hagenbuch B. Gastroenterology. 2001; 120: 525-533Abstract Full Text Full Text PDF PubMed Scopus (646) Google Scholar), OATP-C (8Tamai I. Nezu J. Uchino H. Sai Y. Oku A. Shimane M. Tsuji A. Biochem. Biophys. Res. Commun. 2000; 273: 251-260Crossref PubMed Scopus (557) Google Scholar, 10Abe T. Kakyo M. Tokui T. Nakagomi R. Nishio T. Nakai D. Nomura H. Unno M. Suzuki M. Naitoh T. Matsuno S. Yawo H. J. Biol. Chem. 1999; 274: 17159-17163Abstract Full Text Full Text PDF PubMed Scopus (498) Google Scholar, 11Hsiang B. Zhu Y. Wang Z. Wu Y. Sasseville V. Yang W.-P. Kirchgessner T.G. J. Biol. Chem. 1999; 274: 37161-37168Abstract Full Text Full Text PDF PubMed Scopus (590) Google Scholar, 12König J. Cui Y. Nies A.T. Keppler D. Am. J. Physiol. Gastrointest. Liver Physiol. 2000; 278: G156-G164Crossref PubMed Google Scholar), and OATP8 (13König J. Cui Y. Nies A.T. Keppler D. J. Biol. Chem. 2000; 275: 23161-23168Abstract Full Text Full Text PDF PubMed Scopus (456) Google Scholar) have now been established as the major OATPs located at the basolateral membrane of human hepatocytes. OATP-C (gene SLC21A6), also known as liver specific transporter-1 (LST-1) (10Abe T. Kakyo M. Tokui T. Nakagomi R. Nishio T. Nakai D. Nomura H. Unno M. Suzuki M. Naitoh T. Matsuno S. Yawo H. J. Biol. Chem. 1999; 274: 17159-17163Abstract Full Text Full Text PDF PubMed Scopus (498) Google Scholar) or OATP2 (11Hsiang B. Zhu Y. Wang Z. Wu Y. Sasseville V. Yang W.-P. Kirchgessner T.G. J. Biol. Chem. 1999; 274: 37161-37168Abstract Full Text Full Text PDF PubMed Scopus (590) Google Scholar, 12König J. Cui Y. Nies A.T. Keppler D. Am. J. Physiol. Gastrointest. Liver Physiol. 2000; 278: G156-G164Crossref PubMed Google Scholar), is involved in the hepatic uptake of a broad array of endogenous compounds, such as taurocholate (11Hsiang B. Zhu Y. Wang Z. Wu Y. Sasseville V. Yang W.-P. Kirchgessner T.G. J. Biol. Chem. 1999; 274: 37161-37168Abstract Full Text Full Text PDF PubMed Scopus (590) Google Scholar), estrone sulfate (8Tamai I. Nezu J. Uchino H. Sai Y. Oku A. Shimane M. Tsuji A. Biochem. Biophys. Res. Commun. 2000; 273: 251-260Crossref PubMed Scopus (557) Google Scholar), estradiol 17β-d-glucuronide (10Abe T. Kakyo M. Tokui T. Nakagomi R. Nishio T. Nakai D. Nomura H. Unno M. Suzuki M. Naitoh T. Matsuno S. Yawo H. J. Biol. Chem. 1999; 274: 17159-17163Abstract Full Text Full Text PDF PubMed Scopus (498) Google Scholar), leukotriene C4 (10Abe T. Kakyo M. Tokui T. Nakagomi R. Nishio T. Nakai D. Nomura H. Unno M. Suzuki M. Naitoh T. Matsuno S. Yawo H. J. Biol. Chem. 1999; 274: 17159-17163Abstract Full Text Full Text PDF PubMed Scopus (498) Google Scholar), prostaglandin E2, and thyroid hormone (10Abe T. Kakyo M. Tokui T. Nakagomi R. Nishio T. Nakai D. Nomura H. Unno M. Suzuki M. Naitoh T. Matsuno S. Yawo H. J. Biol. Chem. 1999; 274: 17159-17163Abstract Full Text Full Text PDF PubMed Scopus (498) Google Scholar). Recently, OATP-C has also been shown to mediate the cellular uptake of bilirubin and its glucuronide conjugates (12König J. Cui Y. Nies A.T. Keppler D. Am. J. Physiol. Gastrointest. Liver Physiol. 2000; 278: G156-G164Crossref PubMed Google Scholar, 14Cui Y. König J. Leier I. Buchholz U. Keppler D. J. Biol. Chem. 2001; 276: 9626-9630Abstract Full Text Full Text PDF PubMed Scopus (463) Google Scholar). Furthermore, a variety of drugs and xenobiotics, including the organic anion bromosulfophthalein (9Kullak-Ublick G.A. Ismair M.G. Stieger B. Landmann L. Huber R. Pizzagalli F. Fattinger K. Meier P.J. Hagenbuch B. Gastroenterology. 2001; 120: 525-533Abstract Full Text Full Text PDF PubMed Scopus (646) Google Scholar, 14Cui Y. König J. Leier I. Buchholz U. Keppler D. J. Biol. Chem. 2001; 276: 9626-9630Abstract Full Text Full Text PDF PubMed Scopus (463) Google Scholar), the glycoside oubain (9Kullak-Ublick G.A. Ismair M.G. Stieger B. Landmann L. Huber R. Pizzagalli F. Fattinger K. Meier P.J. Hagenbuch B. Gastroenterology. 2001; 120: 525-533Abstract Full Text Full Text PDF PubMed Scopus (646) Google Scholar), the peptidomimetic BQ-123 (9Kullak-Ublick G.A. Ismair M.G. Stieger B. Landmann L. Huber R. Pizzagalli F. Fattinger K. Meier P.J. Hagenbuch B. Gastroenterology. 2001; 120: 525-533Abstract Full Text Full Text PDF PubMed Scopus (646) Google Scholar), and the HMG-CoA-reductase inhibitor pravastatin (11Hsiang B. Zhu Y. Wang Z. Wu Y. Sasseville V. Yang W.-P. Kirchgessner T.G. J. Biol. Chem. 1999; 274: 37161-37168Abstract Full Text Full Text PDF PubMed Scopus (590) Google Scholar), have been identified as OATP-C substrates. Accordingly, given the extent of its substrate specificity for endogenous and exogenous compounds, it is conceivable that genetic polymorphisms in OATP-C may have significant pharmacologic, toxicologic, and pathologic consequences. In this report, we describe the identification of SNPs inOATP-C and their prevalence in European-American and African-American populations. We show that a number of frequently occurring variant alleles are associated with profound reduction in transport activity. Radiolabeled [3H]estrone sulfate (53 Ci/mmol, >97% purity), [3H]estradiol 17β-d-glucuronide (44 Ci/mmol, >97% purity), and [3H]taurocholate (3.4 Ci/mmol, >97% purity) were purchased from PerkinElmer Life Sciences. [3H]BQ-123 (42 Ci/mmol, >95% purity) was obtained fromAmersham Pharmacia Biotech. [3H]Methotrexate (20 Ci/mmol, 99% purity) was purchased from American Radiolabeled Chemicals (St. Louis, MO). All other chemical and reagents, unless stated otherwise, were obtained from Sigma and were of the highest grade available. A 10-ml sample of blood was obtained from healthy subjects and DNA was isolated using the Qiamp system (Qiagen Inc., Valencia, CA). All subjects were unrelated, healthy, volunteer adults residing in middle-Tennessee who were judged to be healthy on the basis of medical history, physical examination, and laboratory tests indicative of normal cardiac, renal, and liver function. Race was defined by self-reporting (15Senior P.A. Bhopal R. Brit. Med. J. 1994; 309: 327-330Crossref PubMed Scopus (426) Google Scholar). The protocol was approved by the Vanderbilt University Institutional Review Board-Health Sciences, and informed consent was obtained. PCR was carried out using ∼200 ng of human genomic DNA, consisting of dNTPs (0.25 mm each), the specific primer pair (4 μm each), in PCR buffer II (PerkinElmer Life Sciences) with 2.5 mmMgCl2 and 2.5 unit of AmpliTaqTM DNA polymerase (PerkinElmer Life Sciences), in a final reaction volume of 50 μl. The complete oligonucleotide primer sequences are provided in TableI. After the PCR, nonisotopic SSCP analysis was used to identify the presence of OATP-C allelic variants (16Hongyo T. Buzard G.S. Calvert R.J. Weghost C.M. Nucleic Acids Res. 1993; 21: 3637-3642Crossref PubMed Scopus (337) Google Scholar). The gel run time was varied to yield optimal separation of the single strands; for the most part, run times of 4–6 h were sufficient. Variations in the single-strand mobility patterns were clearly visualized.Table ISummary of nonsynonymous polymorphisms in OATP-CExon1-aForward and reverse primers used in PCR of OATP-C exons.PositionGenotyping method1-bForward primers for wild-type (WT) and mutant (MT) variants used in AS-PCR. Reverse primer is found in the left column.Allelic frequency1-cEA, → → to using → → → → → → → → → to using → and reverse primers used in PCR of OATP-C primers for wild-type (WT) and mutant (MT) variants used in AS-PCR. Reverse primer is found in the left to using in a liver from of liver or were in the using of OATP-C was obtained by reverse using the primer pair and from liver were SNPs were to be and the polymorphism was in at A number of from human liver OATP-C for in vitro was to variant known to be and African-American were into the wild-type using the CA). the → → and → were used to and mutant → and → to be in The presence of the was by be defined subjects at a single or multiple were subjects for a at were found to be for at a an allelic was Furthermore, the presence of SNPs in the provided of fragment length polymorphism analysis was used to the genotypic frequencies of The primers on number and restriction used for analysis are in I. PCR was to genotypic frequencies for polymorphisms in were with at a of of in and to for at in well were with of wild-type or variant OATP-C into with and at for The was used as was using drug substrates as R.B. Leake B. Cvetkovic M. Roden M.M. J. A. Wilkinson G.R. J. Pharmacol. Ther. 1999; Google Scholar). In to the estrone sulfate and estradiol 17β-d-glucuronide transport drug uptake the was in the presence of of diffusion was by out experiments using the DNA the transporter and this was from the uptake in the presence of the transporter was carried out to of the uptake and the at the uptake CA). All experiments were carried out in on at to with OATP-C were and the was at for The was with buffer mm mm mm and by were with and of were by on were with a the of OATP-C was by In to sample were and with were using Pharmacia were on and with using a protocol for transport were with mm mm mm and with a at for the were times with mm and for at with the buffer to the After with were with of buffer mm mm mm at for h with of were to of and for h at were times with and the were by of the with buffer for at of the and the were to analysis for of OATP-C and the as of the was using analysis of multiple or as A of was to be the of of sequences revealed the presence of polymorphisms → Asp), → and → on the system by 2000; PubMed Scopus Google Scholar), alleles were and I. Nezu J. Uchino H. Sai Y. Oku A. Shimane M. Tsuji A. Biochem. Biophys. Res. Commun. 2000; 273: 251-260Crossref PubMed Scopus (557) Google and 12König J. Cui Y. Nies A.T. Keppler D. Am. J. Physiol. Gastrointest. Liver Physiol. 2000; 278: G156-G164Crossref PubMed Google 11Hsiang B. Zhu Y. Wang Z. Wu Y. Sasseville V. Yang W.-P. Kirchgessner T.G. J. Biol. Chem. 1999; 274: 37161-37168Abstract Full Text Full Text PDF PubMed Scopus (590) Google Scholar), and 10Abe T. Kakyo M. Tokui T. Nakagomi R. Nishio T. Nakai D. Nomura H. Unno M. Suzuki M. Naitoh T. Matsuno S. Yawo H. J. Biol. Chem. 1999; 274: 17159-17163Abstract Full Text Full Text PDF PubMed Scopus (498) Google Scholar) identify polymorphisms from genomic DNA, SSCP analysis of 14 was in a of European-Americans and The genomic of human using the nonsynonymous polymorphisms → Asp), → T521C (Val-174 → Ala), and G1463C (Gly-488 → were of obtained by reverse from of European-Americans revealed nonsynonymous polymorphisms (T217C (Phe-73 → Leu), T245C (Val-82 → Ala), → Gly), T1058C (Ile-353 → (Asn-432 → Asp), A1385G (Asp-462 → Gly), → Gly), and → the basis of alleles were to associated with and were the of In a number of SNPs in OATP-C were including and in SSCP of T521C for wild-type and analysis of show restriction patterns for and mutant a of and PCR, the genotypic frequencies of OATP-C SNPs were variants were found at a relatively high T521C and their genotypic frequencies to be dependent on and G1463C polymorphisms were in the was for and T521C The most polymorphisms in were and G1463C the and T521C (14%) were European-Americans. nonsynonymous polymorphisms were at genotypic frequencies in this and their be to the at a frequency in African- European-Americans was in European-Americans array of OATP-C allelic variants was expressed using the system was capable of transporting known including estrone and estradiol 17β-d-glucuronide Moreover, we found that is a substrate for OATP-C the transport of the OATP-C we on estrone sulfate and estradiol as to be the most substrates the compounds estrone sulfate transport of the and were from other For estradiol transport with and were and a number of other OATP-C variants and estrone sulfate transport were the were for estradiol 17β-d-glucuronide that now transport and was from the For the of the transport activity were associated with alterations in OATP-C analysis indicated a of the of and estrone sulfate uptake A was with the of to be that of the other with its transport activity. In OATP-C the with a that is in with that the was of the with in the of the major and the of a single that OATP-C was in human liver the OATP-C with with of and For a the uptake of estrone sulfate was for allelic and the are in variants those obtained with for variant and in to the in transport for OATP-C variants are with other substrates estrone uptake were also using estradiol 17β-d-glucuronide. In were for the of estradiol 17β-d-glucuronide OATP-C variants with estrone sulfate for estradiol 17β-d-glucuronide were for and variants with and for the most part, this was to decreased of the transport with the we were to that that → → → → and → reduced estrone sulfate transport of for allelic variants of amino acid were markedly and from to of the For the it was to → → were important for the reduced OATP-C for [3H]estrone sulfate transport by OATP-C were obtained as The for are the for are of and the are of 4–6 for variant to in a were obtained as The for are the for are of and the are of 4–6 for variant to the of reduced transport activity for OATP-C variants to be associated with alterations in the of the cellular of this transporter in surface for the decreased transport of variant OATP-C Accordingly, surface biotinylation experiments were to plasma membrane associated The for such experiments revealed that the plasma membrane of and were markedly reduced in to analysis indicated that the of surface of and from to of that for the were of a the major in was in to the major from human The of surface within was by the of in the it that the of expressed in with this within and that and of OATP-C are most on the Furthermore, decreased surface of OATP-C variants is associated with altered transport function. has been the presence or of genetic polymorphisms members of the transporter family, increasing a role of transporters in the hepatocellular uptake of endogenous compounds and drugs. In this report, we describe the identification of 14 nonsynonymous polymorphisms in analysis of subjects of and African-American revealed that SNPs in OATP-C are that their frequencies to race. Given the number of polymorphisms in the and the that polymorphisms be we for OATP-C alleles on the of 2000; PubMed Scopus Google Scholar). the first sequences for OATP-C are The were OATP-C to the transport of OATP-C variants was in the and variants markedly estrone sulfate uptake the wild-type altered transport was with the substrate estradiol 17β-d-glucuronide. be that estrone sulfate and estradiol 17β-d-glucuronide a substrate specificities for hormone conjugates may be markedly for a For example, OATP-B estrone sulfate estradiol 17β-d-glucuronide (8Tamai I. Nezu J. Uchino H. Sai Y. Oku A. Shimane M. Tsuji A. Biochem. Biophys. Res. Commun. 2000; 273: 251-260Crossref PubMed Scopus (557) Google Scholar,9Kullak-Ublick G.A. Ismair M.G. Stieger B. Landmann L. Huber R. Pizzagalli F. Fattinger K. Meier P.J. Hagenbuch B. Gastroenterology. 2001; 120: 525-533Abstract Full Text Full Text PDF PubMed Scopus (646) Google Scholar). Given that the transport of substrates were by specific OATP-C it is that other substrates may analysis of the transport it is that at and have consequences. of amino are the and of as well as other members of the family that to the transmembrane-spanning domains and were associated with a significant reduction in transport activity. the G1463C (Gly-488 → to be located on extracellular loop was associated with a significant reduction in to the wild-type the → amino acid in an of the that be a for members of the transporter family the presence of such a in a extracellular with the that this and an SNPs identified in this (Asn-432 → and → were associated with a in or in an important role of this to is in to the SNPs in extracellular loop → → → and → Gly), associated with or changes in the transport activity. In of expressed of variant other we in the expressed of the surface biotinylation experiments were carried several OATP-C variants and were found to have decreased membrane as with the wild-type in part, the alterations in transport activity. For example, the were reduced for transport of and estradiol 17β-d-glucuronide that the → altered surface transport activity. For the most part, in the were OATP-C variants with reduced surface that the also the and of this be to amino acid in OATP-C transporter and and such in vitro also to The of functionally in population for the most part, relatively high allelic frequency was for the T521C (Val-174 → transition in European-Americans (14%) and the G1463C transversion (Gly-488 → of the polymorphisms that are associated with transport in vitro have in are a of the extent of hepatic uptake the drug polymorphisms in an uptake transporter such as OATP-C may be important hepatic drug is by as in the for the OATP-C substrate pravastatin (11Hsiang B. Zhu Y. Wang Z. Wu Y. Sasseville V. Yang W.-P. Kirchgessner T.G. J. Biol. Chem. 1999; 274: 37161-37168Abstract Full Text Full Text PDF PubMed Scopus (590) Google Scholar, M. S. R. Y. Pharm. Res. (N. Y.). PubMed Scopus Google Scholar). is that as drugs are identified as OATP-C the of genetic in OATP-C to in drug disposition In the of OATP-C in to other OATPs in the hepatic uptake of drugs also be Accordingly, the substrate specificities for hepatic OATPs and their polymorphisms to be Moreover, involved in the of OATP-C to be defined and be into to the of OATP-C In a report, Cui Y. König J. Leier I. Buchholz U. Keppler D. J. Biol. Chem. 2001; 276: 9626-9630Abstract Full Text Full Text PDF PubMed Scopus (463) Google Scholar) that OATP-C was capable of transporting the that OATP-C polymorphisms may be to a of in the of bilirubin to be for the to P.J. C. S. A. D. J. Med. PubMed Scopus Google Scholar), a in a bilirubin uptake is also to to the of this Wolkoff A.W. B.F. J. Gastroenterology. 70: Full Text PDF PubMed Scopus Google Scholar, M. E. I. A. R. P.J. C. J.D. Hepatology. 2001; PubMed Scopus Google Scholar). a role for OATP-C is other human OATPs have been shown to be capable of transporting bilirubin M. E. I. A. R. P.J. C. J.D. Hepatology. 2001; PubMed Scopus Google Scholar). a role for OATP-C as a of In we the identification and of polymorphisms in human this the first examination of polymorphisms in a hepatic uptake transporter and the for of the polymorphisms in genetic variants of OATP-C are and their frequencies are defined in of of and allelic we that the presence of variant other uptake to in drug disposition and certain We F. for human liver and for We also R. Wilkinson for the