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Regular Article Tissue-Speciˆc Mrna Expression Proˆles of Human ATP-Binding Cassette and Solute Carrier Transporter Superfamilies

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Regular Article Tissue-Speciˆc Mrna Expression Proˆles of Human ATP-Binding Cassette and Solute Carrier Transporter Superfamilies Drug Metab. Pharmacokinet. 20 (6): 452–477 (2005). Regular Article Tissue-speciˆc mRNA Expression Proˆles of Human ATP-binding Cassette and Solute Carrier Transporter Superfamilies Masuhiro NISHIMURA* and Shinsaku NAITO Division of Pharmacology, Drug Safety and Metabolism, Otsuka Pharmaceutical Factory, Inc., Naruto, Tokushima, Japan Full text of this paper is available at http://www.jstage.jst.go.jp/browse/dmpk Summary: Pairs of forward and reverse primers and TaqMan probes speciˆc to each of 46 human ATP- binding cassette (ABC) transporters and 108 human solute carrier (SLC) transporters were prepared. The mRNA expression level of each target transporter was analyzed in total RNA from single and pooled specimens of various human tissues (adrenal gland, bone marrow, brain, colon, heart, kidney, liver, lung, pancreas, peripheral leukocytes, placenta, prostate, salivary gland, skeletal muscle, small intestine, spinal cord, spleen, stomach, testis, thymus, thyroid gland, trachea, and uterus) by real-time reverse transcription PCR using an ABI PRISM 7700 sequence detector system. In contrast to previous methods for analyzing the mRNA expression of single ABC and SLC genes such as Northern blotting, our method allowed us to perform sensitive, semiautomatic, rapid, and complete analysis of ABC and SLC transport- ers in total RNA samples. Our newly determined expression proˆles were then used to study the gene expression in 23 diŠerent human tissues, and tissues with high transcriptional activity for human ABC and SLC transporters were identiˆed. These results are expected to be valuable for establishing drug transport-mediated screening systems for new chemical entities in new drug development and for research concerning the clinical diagnosis of disease. Key words: ABC transporter; SLC transporter; mRNA expression; tissue distribution; quantiˆcation Table 1. It has now become clear that some transporters Introduction are responsible for drug transport in various tissues, and Transporters play a vital role in the absorption, they may be key determinants of the pharmacokinetic distribution, and excretion processes that largely characteristics of drugs in terms of intestinal absorp- determine the pharmacodynamics and pharmacokinet- tion, tissue distribution, and elimination.12–14) These icsofdrugs.ForanydrugtohaveaneŠect,itmust transporters may therefore be promising candidates for reach the target organ at su‹cient concentrations. drug delivery. The assessment of the protein levels andW Drug transporters such as ATP-binding cassette (ABC) or transport capacity of each ABC and SLC transporter transporters and solute carrier (SLC) transporters are is important in selecting transporters that may be selectively expressed in many tissues such as the brain, involved in absorption, distribution, and elimination. intestine, kidney, liver, placenta, and testis.1–5) These However, such assessment of these ABC and SLC trans- transporters transport a variety of substrates, including porters in the same sample is di‹cult because a large amino acids, lipids, inorganic ions, peptides, saccha- amount of sample is required for measurement. Thus, rides, metals, drugs, toxic xenobiotics, chemical com- we considered that rapid estimation should be possible pounds, and proteins.6–10) For example, it is known that by the detailed evaluation of the mRNA expression SLC2As and SLC5As are transporters for saccharides,9) levels of each transporter in target tissues based on the SLC1As, SLC6As, SLC7As, SLC36As and SLC38As ˆndings of previous studies, followed by the evaluation are for amino acids,10) SLC15As are for peptides,7,9) and of protein levels and transport capacity levels. There- SLC28As and SLC29As are for nucleosides.11) The fore, the study of the tissue-speciˆc mRNA expression nomenclature of these transporters is summarized in proˆles of drug transporters could provide important Received; July 29, 2005, Accepted; September 17, 2005 *To whom correspondence should be addressed:MasuhiroNISHIMURA,Ph.D.,Division of Pharmacology, Drug Safety and Metabolism, Otsuka Pharmaceutical Factory, Inc., Naruto, Tokushima 772-8601, Japan. Tel. ＋81-88-685-1151 ext. 624, Fax. ＋81-88-686-8176, E-mail: nisimums＠ otsukakj.co.jp 452 mRNA Expression Proˆles of Human Drug Transporters 453 Table 1. Nomenclature of Target Genes Abbreviation Trivial Name(s) ATP-binding cassette (ABC) transporters ABCA1 TGD,ABC1,CERP,ABC-1,HDLDT1 ABCA2 ABC2 ABCA3 ABC3, ABC-C, LBM180, MGC72201, EST111653 ABCA4 FFM, RMP, ABCR, RP19, STGD, ABC10, STGD1, DKFZp781N1972 ABCA5 ABC13, EST90625 ABCA6 EST155051 ABCA7 ABCX, ABCA-SSN ABCA8 KIAA0822 ABCA9 EST640918 ABCA10 EST698739 ABCA12 LI2, ICR2B, DKFZp434G232 ABCB1 CLCS, MDR1, P-gp, PGY1, ABC20, CD243, GP170, Pgp1 ABCB2 TAP1, APT1, PSF1, ABC17, RING4, TAP1N, D6S114E ABCB3 TAP2, APT2, PSF2, ABC18, RING11, D6S217E ABCB4 MDR3, PGY3, ABC21, MDR2W3, PFIC-3, Pgp3 ABCB5 ABCB5beta, EST422562 ABCB6 PRP, umat, ABC14, MTABC3, EST45597 ABCB7 ABC7, ASAT, Atm1p, EST140535 ABCB8 MABC1, M-ABC1, EST328128 ABCB9 TAPL, KIAA1520, EST122234 ABCB10 M-ABC2, MTABC2, EST20237 ABCB11 BSEP, PGY4, SPGP, ABC16, PFIC2 ABCC1 MRP, ABCC, GS-X, MRP1, ABC29, DKFZp781G125 ABCC2 DJS, MRP2, cMRP, ABC30, CMOAT, KIAA1010 ABCC3 MLP2, MRP3, ABC31, MOAT-D, cMOAT2, EST90757 ABCC4 MRP4, MOATB, MOAT-B, EST170205 ABCC5 MRP5, SMRP, ABC33, MOATC, MOAT-C, pABC11, EST277145 ABCC6 ARA, PXE, MLP1, MRP6, ABC34, MOATE, EST349056 ABCC7 CFTR, CF, ABC35, TNR-CFTR, dJ760C5.1 ABCC8 HI, SUR, PHHI, SUR1, ABC36, HRINS ABCC9 SUR2, ABC37, FLJ36852 ABCC10 MRP7, SIMRP7, EST182763 ABCC11 MRP8 ABCC12 MRP9 ABCD1 ALD,AMN,ALDP,ABC42 ABCD2 ALDR, ABC39, ALDL1, ALDRP, hALDR ABCD3 ABC43, PMP70, PXMP1 ABCD4 P70R, P79R, ABC41, PMP69, PXMP1L, EST352188 ABCE1 RLI, OABP, ABC38, RNS41, RNASEL1, RNASELI, RNASELIOABP ABCF1 ABC27, ABC50, EST123147 ABCF2 ABC28, M-ABC1, HUSSY-18, EST133090, DKFZp586K1823 ABCG1 WHITE1, ABC8, MGC34313 ABCG2 MRX, MXR, ABCP, BCRP, BMDP, MXR1, ABC15, BCRP1, EST157481, MGC102821 ABCG4 WHITE2 ABCG5 ABCG8 Solute carrier (SLC) transporters SLC1A1 EAAC1, EAAT3 SLC1A2 EAAT2, GLT-1 SLC1A3 EAAT1, GLAST, GLAST1 SLC1A4 SATT, ASCT1 SLC1A5 R16, ATB9, M7V1, RDRC, ASCT2, M7VS1 SLC2A1 GLUT, GLUT1 SLC2A2 GLUT2 SLC2A3 GLUT3 SLC2A4 GLUT4 SLC2A5 GLUT5 SLC2A7 GLUT7 continued 454 Masuhiro NISHIMURA and Shinsaku NAITO Table 1. (continued) Abbreviation Trivial Name(s) SLC2A8 GLUT8, GLUTX1 SLC2A9 GLUT9, GLUTX SLC2A10 GLUT10 SLC2A11 GLUT11 SLC2A12 GLUT12 SLC2A13 HMIT SLC2A14 GULT14 SLC3A1 D2H, ATR1, NBAT, RBAT, CSNU1 SLC3A2 4F2, CD98, MDU1, 4F2HC, 4T2HC, NACAE SLC4A1 DI, WD, AE1, WD1, BND3, EPB3, CD233, EMPB3, RTA1A SLC4A2 AE2, HKB3, BND3L, NBND3, EPB3L1 SLC4A3 AE3, SLC2C SLC4A4 KNBC, NBC1, pNBC, HNBC1, hhNMC SLC4A7 NBC2, NBC3, SBC2 SLC4A8 NBC3 SLC4A9 AE4 SLC4A10 SLC4A11 BTR1, dJ794I6.2 SLC5A1 NAGT, SGLT1, D22S675 SLC5A2 SGLT2 SLC5A3 SMIT, SMIT2 SLC5A4 SAAT1, SGLT3, DJ90G24.4 SLC5A5 NIS SLC5A6 SMVT SLC5A7 CHT, CHT1, hCHT SLC5A8 AIT SLC5A10 SGLT5, FLJ25217 SLC5A11 KST1, RKST1, SGLT6, SMIT2 SLC5A12 MGC52019 SLC6A2 NET, NAT1 SLC6A3 DAT, DAT1 SLC6A4 OCD1, SERT, 5-HTT SLC6A5 NET1, GLYT2 SLC6A6 TAUT SLC6A7 PROT SLC6A9 GLYT1 SLC7A1 ERR, ATRC1, CAT-1, HCAT1, REC1L SLC7A2 ATRC2, CAT-2, HCAT2 SLC7A3 ATRC3, CAT-3, FLJ14541 SLC7A4 CAT4, CAT-4, HCAT3 SLC7A5 E16, CD98, LAT1, MPE16, D16S469E SLC7A6 LAT3, LAT-2, y＋LAT-2, KIAA0245 SLC7A7 LPI, LAT3, Y＋LAT1, y＋LAT-1 SLC7A8 LAT2, LPI-PC1 SLC7A9 CSNU3 SLC7A10 asc-1, HASC-1, FLJ20839 SLC7A11 xCT, CCBR1 SLC7A13 AGT1, XAT2, AGT-1 SLC10A1 NTCP, NTCP1 SLC10A2 ASBT, ISBT, NTCP2 SLC10A3 P3, DXS253E SLC10A4 MGC29802 SLC10A5 P5 SLC15A1 PEPT1, HPECT1, HPEPT1 SLC15A2 PEPT2 SLC15A3 PHT2, PTR3, hPTR3 SLC15A4 PHT1, PTR4 SLC21A3 OATP, OATP-A, OATP1A2, SLCO1A2 SLC21A6 LST-1, OATP2, OATP-C, OATP1B1 SLC21A9 OATPB, OATP-B, OATP2B1, KIAA0880 continued mRNA Expression Proˆles of Human Drug Transporters 455 Table 1. (continued) Abbreviation Trivial Name(s) SLC21A11 OATP-D, OATP3A1, SLCO3A1 SLC21A12 POAT, OATP1, OATP-E, OATP4A1, OATPRP1 SLC21A14 OATP1, OATP-F, OATP1C1, SLCO1C1 SLC21A15 OATP-J, OATP5A1, OATPRP4 SLC22A1 OCT1, HOCT1 SLC22A2 OCT2, MGC32628 SLC22A3 EMT, EMTH, OCT3 SLC22A4 OCTN1, MGC34546 SLC22A5 CDSP, OCTN2, FLJ46769 SLC22A6 OAT1, PAHT, HOAT1, ROAT1, MGC45260 SLC22A7 NLT, OAT2, MGC24091, MGC45202 SLC22A8 OAT3, MGC24086 SLC22A9 OAT4, ust3, HOAT4, UST3H SLC22A11 hOAT4, MGC34282 SLC22A12 RST, OAT4L, URAT1 SLC22A13 OCTL1, OCTL3, ORCTL3 SLC22A14 OCTL2, OCTL4, ORCTL4 SLC22A15 FLIPT1, PRO34686, DKFZp761G0313 SLC22A16 CT2, OCT6, OKB1, FLIPT2, dJ261K5.1 SLC22A17 BOCT, BOIT, hBOIT SLC22A18 HET, ITM, BWR1A, IMPT1, TSSC5, ORCTL2, BWSCR1A, SLC22A1L, p45-BWR1A SLC28A1 CNT1, HCNT1 SLC28A2 CNT2, HCNT2, SPNT1, HsT17153 SLC28A3 CNT3 SLC29A1 ENT1 SLC29A2 ENT2, DER12, HNP36 SLC29A3 ENT3, FLJ11160 SLC29A4 ENT4, PMAT, FLJ34923 SLC36A1 PAT1, LYAAT1 SLC36A2 PAT2, TRAMD1 SLC36A3 PAT3, TRAMD2, tramdorin2 SLC36A4 PAT4, FLJ38932 SLC38A1 ATA1, NAT2, SAT1, SNAT1 SLC38A2 ATA2, SAT2, SNAT2, PRO1068, KIAA1382 SLC38A3 G17, SN1 SLC38A4 ATA3, NAT3, PAAT, FLJ10191 SLC38A5 SN2, JM24, pp7194 SLC38A6 NAT-1 information concerning the mechanisms of drug dispo- spinal cord, spleen, stomach, testis, thymus, thyroid sition. However, the tissue distribution of the mRNA gland, trachea, and uterus) was purchased from expression of large numbers of human ABC and SLC CLONTECH Laboratories, Inc. (Hilden, Palo Alto, transporters has not been evaluated under the same CA, USA). The total RNA source information for these experimental conditions. human tissues is shown in Table 2.YeasttRNAwas The present study was therefore undertaken to inves- purchased from
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