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 transporters 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 Life Technologies, Inc. (Rockville, tigate the mRNA expression levels of 46 human ABC MD, USA), and the TaqMan One-Step RT-PCR Master transporters and 108 human SLC transporters using mix reagents kit was purchased from Applied high-sensitivity real-time reverse transcription PCR Biosystems (Foster City, CA, USA). All other chemicals (RT-PCR) in total RNA from single and pooled speci- used in this study were of reagent grade. mens of 23 adult human tissues. Oligonucleotides: The pairs of primers and the TaqMan probes for b-actin and glyceraldehyde 3- Materials and Methods phosphate dehydrogenase (GAPDH) used for RT-PCR Materials: Total RNA prepared from single and analysis employed sequences that have been reported pooled specimens of adult human tissues (adrenal previously.15) The pairs of primers and the TaqMan gland, bone marrow, brain, colon, heart, kidney, liver, probes for b-2-microglobulin (B2M), b-glucuronidase lung, pancreas, peripheral leukocytes, placenta, (GUSB), hypoxanthine phosphoribosyltransferase 1 prostate, salivary gland, skeletal muscle, small intestine, (HPRT1), peptidylprolyl isomerase A (PPIA), and 456 Masuhiro NISHIMURA and Shinsaku NAITO

Table 2. Total RNA Source Information for Various Tissues

Tissue Pool size Age Sex Race Adrenal gland 61 15–61 years female, male Caucasian Bone marrow 8 18–56 years female, male Caucasian Brain 1 43 years male Caucasian Colon 1 35 years female Caucasian Heart 10 21–51 years female, male Caucasian Kidney 14 18–59 years female, male Caucasian Liver 1 51 years male Caucasian Lung 3 15–40 years female, male Caucasian Pancreas 2 50, 55 years male Caucasian Peripheral leukocytes 250 18–40 years female, male Caucasian Placenta 8 19–39 years female Caucasian Prostate 32 21–50 years male Caucasian Salivary gland 24 15–60 years female, male Caucasian Skeletal muscle 7 20–68 years female, male Caucasian Small intestine 5 20–61 years female, male Caucasian Spinal cord 49 15–66 years female, male Caucasian Spleen 14 30–66 years female, male Caucasian Stomach 1 50 years male Caucasian Testis 39 14–64 years male Caucasian Thymus 3 20–38 years male Caucasian Thyroid gland 65 15–61 years female, male Caucasian Trachea — 18–54 years female, male Caucasian Uterus 3 40–61 years female Caucasian

—, no data available.

transferrin receptor (TFRC) used for RT-PCR analysis RNA at 25,000 pg per 50 mL of reaction mixture was also employed sequences that have been reported used for measurement of the target mRNA in each previously.16) The pairs of primers and the TaqMan tissue. The RT-PCR assay was performed using the probes for ABCA1, ABCA2, ABCA4, ABCA8, ABI PRISM 7700 Sequence Detector system (Applied ABCB1, ABCB2, ABCB3, ABCB4, ABCB6, ABCB7, Biosystems) under the same conditions as in our previ- ABCB8, ABCB11, ABCC1, ABCC2, ABCC3, ABCC5, ous studies.15,16,18) ABCC6,ABCC9,ABCD1,ABCD3,ABCD4,ABCE1, Data analysis: Samples were deemed positive at any ABCF1, ABCF2, ABCG1, ABCG2, SLC22A1, given cycle when the value of the emitted ‰uorescence SLC22A3, and SLC22A5 used for RT-PCR analysis was greater than the threshold value calculated by the also employed sequences that have been reported instrument's software (Sequence Detector Ver. 1.9.1). previously.17) The pairs of primers and the TaqMan The threshold cycle (Ct), which is deˆned as the cycle at probes for the target mRNAs were designed based on which PCR ampliˆcation reaches a signiˆcant value the human mRNA sequence (Table 3)usingPrimer (i.e., usually 15 times greater than the standard devia- Express software (Applied Biosystems). The GenBank tion of the baseline), is given as the mean value. The accession number and the position from the initiation relative expression of each mRNA was calculated by the codon are also shown in Table 3.EachprimerandWor DCt method (where DCt is the value obtained by probe was homology searched by an NCBI BLAST subtracting the Ct value of PPIA mRNA from the Ct search to ensure that it was speciˆc for the target mRNA value of the target mRNA), as employed in previous transcript. The primers and TaqMan probes were studies.15,19–21) Speciˆcally, the amount of target mRNA synthesized by the Genosys Division of SIGMA- relative to PPIA mRNA is expressed as 2－(DCt).Dataare ALDRICH JAPAN K.K. (Ishikari, Hokkaido, Japan). expressed as the ratio of the target mRNA to PPIA The TaqMan probes contained 6-carboxy‰uorescein mRNA. (FAM)atthe5? end and 6-carboxytetramethylrhoda- Results and Discussion mine (TAMRA) at the 3? end and were designed to hybridize to a sequence located between the PCR In this study, we investigated the mRNA expression primers. levels of 46 human ABC family transporters and 108 TaqMan RT-PCR conditions: Total RNA samples human SLC family transporters in adult human tissues. obtained from adult human tissues were diluted under Analysis was conducted by RT-PCR using the ABI the same conditions as in our previous studies.15,16) Total PRISM 7700 Sequence Detector System in the presence mRNA Expression Proˆles of Human Drug Transporters 457 continued (1371–1405) ? (2124–2157) (1421–1453) ? (1348–1381) (1355–1387) ? ? (1315–1346) ? (563–594) (1274–1304) ? (4263–4293) (1152–1181) ? (525–554) ? (714–743) (2396–2425) ? ? (1367–1396) (1131–1160) (883–911) (990–1019) (2448–2476) ? ? ? (398–425) (744–771) ? (4484–4511) (603–630) ? (1713–1741) (565–592) ? ? (2522–2549) ? (575–602) (1011–1038) (169–196) (880–906) ? ? (3203–3230) ? ? ? ? ? ? ? (3159–3185) (2256–2281) ? ? (850–876) ? (569–594) (153–178) (242–267) (1036–1061) (1780–1805) (1064–1089) ? ? (1051–1076) (922–946) (1018–1043) ? (1398–1422) (2846–2870) ? ? ? ? ? ? ? ? ? ? ? (273–296) (1289–1312) (1138–1160) (4099–4121) (1355–1377) ? ? (1189–1211) ? ? ? ? -TGTGCCAAATGGAACACGGAGGA-3 -AGCAGGTGTTCGACAATGGCAGCATC-3 -AACGCCGAATATAATCCCAAGCGGTTTG-3 -CTCACGCCTCCATTGTGGTCTCCAACTT-3 -AGGCAGAGGCTGTCTGTGATCGAGTAGC-3 -CCCATGCTGACGTTGAGGGAACA-3 -CCATGAATGCCACTTCCCAAACAAGC-3 -TTCCCAGCTACGGATTTCAGGCCTCTA-3 -TTATCGGCATGAGCAGCATCAGCGA-3 -AGTCTGTATGCAGCACGACGTCTTGTTCAGT-3 -CCTTGATAAAGCCAGGACGGGAAGGA-3 -CTGCGGAACACAGTCAAGGTCACGG-3 -AATGCAGTTAGCAAGGAAAGAGGCAGTCGC-3 -TCGGAAGGCACTTCGTCTTAGTAACATGGC-3 -ATGAAGGACTTGCATTGGCACATTTCGT-3 -TCCAGTGTGGTCCGATCTACCGTCAA-3 -CCTTGCACGTGTACCAAGCTTACTGGAA-3 -CAGCTGGAGGTTACATGGTCTCTTGCATAA-3 -CCCAACCAGAAGACCCAGATACTGTCTTGCT-3 -AAAGCATTGTGGAAAAGAAGCCTCGGAC-3 -ATCTACCAGGTTGGCTTGATCCCCAGTC-3 -TCTTCATGAGGGAGCACCTCAACTACTGGTACA-3 -TTCAATGACTGCGGTTACCCTTGTCCT-3 -AGAGGGCAATGCTTTACTATGAACTGGAAGACG-3 -CTCGATTCGTGTTACCCGTTGGTGCA-3 -TGGGATGAACGTCTTAGGTCTGATAGGGTT-3 -CATCGTCTTGCCACTCCTCTACTTCTTGGT-3 -CAGCAGCTCTGGAAATGTAACCCATGAA-3 -CGAGAAATATCTTCCCTTCCAACCTGGTGTCA-3 -CCGGCGGAATTCAATGCTGATGAT-3 -ACCTGTTTATGCAACCATTGGAGTTGGC-3 -ATCTTCAAGGATGCAGGTGTTCAAGAGCC-3 -ATTGGCCCTGGCCCCATTCCTTG-3 -CTCCTCACCACCATCTACATCTTCTTGATTGTCC-3 -ACGGGAAGCTCATGCTGCTTCTATGG-3 -CTGTGTCCCTGAAACTAAAGGAAAGACTCTGGAAC-3 -CAGGTGGCATCCCGTTCATCTTGA-3 -ACAGCTTCAACTGGGCGGCCAAC-3 -CCATCTACACTGGCCTGTTCCTTCCTGAGA-3 -TCCTCTGTGATGGCAGCTTCGTTGGT-3 -TCAGAAAGGACAGACTCAGAAGGCCCGT-3 -CTGTACCATGACTTCACCACCACGCA-3 -CTGACTTCCTTCTTGCCGGCTCAACT-3 -CAAGTATCACCCAGATGTGCCCTACGTCA-3 -AAAGGTTCCACACAGAGTGGCCGAGAA-3 -AAACCCATCGAGCTCCAGCATGAAC-3 -ACTAATTGTGCCAAGTGAGTTCAAGCCAACAAGT-3 -TTGGAAAGGCCAATAATTGCATTTGTGAGACT-3 -TTTCCTGTGTATTGTCCTTGTGGCAACTG-3 -CTTCTCGGCCGTACTCTACATTTACCTGGC-3 ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? (799–775) 5 (1779–1756) 5 ? (3236–3214) 5 ? (705–683) 5 (231–209)(2915–2893) 5 5 (1477–1455) 5 (587–565) 5 ? (1075–1054) 5 (1211–1190) 5 ? ? ? ? (648–628) 5 (289–269) 5 (2607–2587)(475–455) 5 5 (615–595)(1110–1090) 5 5 (4378–4357) 5 ? (1052–1032) 5 ? (647–627) 5 (319–299) 5 (345–325) 5 ? (2324–2304) 5 (1190–1170) 5 (4534–4514) 5 (1415–1395) 5 (1427–1407) 5 (1097–1077) 5 (1183–1163) 5 (1008–988) 5 (933–913) 5 (3279–3259) 5 (1153–1133) 5 (1837–1817) 5 (1409–1389) 5 ? ? (997–978) 5 (1282–1263) 5 (1401–1382) 5 ? ? ? ? (628–608) 5 ? ? (1461–1442) 5 ? ? ? ? (1149–1130) 5 (948–929) 5 ? ? (1328–1309) 5 ? ? ? ? ? ? (1416–1397) 5 ? ? ? ? (2449–2431) 5 ? ? ? ? (770–752) 5 (2507–2489)(2181–2163) 5 5 ? (4142–4124) 5 ? ? (1372–1354) 5 (1442–1424) 5 ? ? ? ? ? ? ? ? ? -CAGTGCTCACATGGCTGACTT-3 -CAGGAAGCGAGAATGCAGAGT-3 -TGGTTCGTGGCTCTCTTATCC-3 -CTCGTTAAACTGGTCCTTGGC-3 -TTAACTGCCCAGACACCATGA-3 -ACGGCAGCATACACCTCCA-3 -CACATTACAGATGAGACCCTGGA-3 -AAGTACAGGGAAACATCCACCAG-3 -CAGAGGCCTGAAATCCATAACTG-3 -TTACTTCCTCGTGGAGCTGCTT-3 -GCGTTCTGAATTGCAGAGAGC-3 -AGGTGACCAAGGAGAGCTGC-3 -AGCCCAGTTGCTCCAAAGAAAC-3 -TTGACTATCTGGCCTGTGGTTGT-3 -CAGATTAGCCCCATGAGGAGT-3 -ACTCGCTTAGCTTTTGCACGC-3 -GGCTTGCATGAGAAGCAGAGA-3 -CGATCAGCACCACGAAGAA-3 -CATGTCAAGGTGGCATTTGC-3 -AGGTAGCAGGGATGGCAATCA-3 -GCAGGTTGCAGGTGAACTGAT-3 -GTCTTGGCCAGGTAATACGCT-3 -GCTTTGGGTATCCACTGACGT-3 -AATATGGACCAGTGGTGTACAGC-3 -CTGTGCAATAAACACCGCTG-3 -CCCATAGCGATGCCAAAAG-3 -CCTCCAATAAAAACCCAAGGG-3 -CACTCCTAACACCAGAGCAAACA-3 -AGAGTATGAGCGAAAGGCTGC-3 -CAGTTTCGAGAAGCCCATGAG-3 -TAGAAAGAGAGAACGTCGCCC-3 -AGTATTAACCACACCCGCGC-3 -AGTTGGAGAAACCAGCCACA-3 -TCTATGAACGTCTTGGCCTTG-3 -GAAACATGGAGACGGTGCAAG-3 -CCCTCAAAATGGGCTGTGATT-3 -TGACGGTGCCTGCAATGAT-3 -GACAGCGGTCAGTCCGTAGA-3 -TTGGAAGGTCTTGCCTTTGG-3 -AGATTTACGATGCCCATGGTC-3 -GGTTACCACGCATCTGAGATAAAAT-3 -CTTCAGTCCCCATGAACCTGT-3 -GGGTGAAGAGCATCAGCTGGTA-3 -AATAAGTGCATGCGCCAGG-3 -CTGGTTTTTGTCCAGGAGCAA-3 -TGATGATTCCCCAGAACCG-3 -TGGAACGAACCAACCTCGG-3 -AAACCTGGTTGGAACAGGGA-3 -AGTGAAACGGGTAATGTAGCAGAC-3 -CCCCCAAAAGTGATGGCATTA-3 ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? Primers and Probes Used for RT-PCR Analysis Table 3. (855–881) 5 ? (1391–1415) 5 (574–597) 5 ? ? (4231–4252) 5 (1128–1149) 5 (199–520) 5 (1330–1352) 5 (38–59) 5 (2372–2393) 5 (2487–2507)(146–167) 5 5 (2823–2844) 5 (1750–1771) 5 (1042–1062) 5 ? (2232–2252) 5 (374–394) 5 (1014–1034) 5 ? (3122–3142) 5 ? ? (994–1014) 5 (1096–1116)(3120–3140) 5 5 (896–916) 5 (532–552) 5 ? (494–514)(1252–1272) 5 5 ? (1374–1394) 5 (4452–4472) 5 (1683–1703) 5 ? ? (1328–1348) 5 (967–987) 5 ? ? ? (691–710) 5 (1333–1353) 5 (2414–2434)(858–877) 5 5 ? (2095–2114) 5 ? ? ? ? (541–560) 5 (982–1001) 5 ? ? ? ? ? ? ? ? ? ? ? (246–265) 5 (1325–1344) 5 (547–566) 5 (1265–1284) 5 ? (220–238) 5 ? ? (1292–1310) 5 ? (4075–4093) 5 (1021–1039)? 5 (829–847) 5 ? ? (718–736) 5 (1094–1112) 5 (1335–1353) 5 (1168–1186) 5 ? ? ? ? ? ? ? ? ? ? ? ? ? 153449) – -GGCTGCATCACCATCATAGGT-3 -TTCTCCTTTGGGCTGGTCAT-3 -AAGACCATTGCACTTCGTGC-3 -CTTGTTCAACAACCAGGCGTA-3 -GGCTGCTATTCTGACCACTCA-3 -TGCCCTCAAGAGAACGTGC-3 -AGAATTTCATGTATCGCCGGAG-3 -CAATGAGCAGCATTGGTGACT-3 -GATCACAAACTGCGTTTCTCCT-3 -ACAGACCTACACACGGTACGGA-3 -CAGTGAGAAGGTGGTTCAGCA-3 -TGGTCTCCCAGAACATCAATG-3 -ATATGCCAGCAAAGTGGACCAT-3 -CGAGTAGCCATGTGCCATATGA-3 -TAAAGCTGTCAAGCCGTGTTC-3 -CATATCTTGGTCACACCGCTGT-3 -GCTGCAGGAAGAAAGCAAGAA-3 -GGGTCTACCACCACTACATCCA-3 -AAAAGCCCCCCATCTTACATC-3 -CTGGTCTGGATGGAAAAATCG-3 -TGACCCTACTGGAGCAATTTGT-3 -TGCTCACCTTCCCCTTAGAGA-3 -CCAGCGGAAATGCTTGATT-3 -TTCTGGATGTCATCTCCAAATGTTA-3 -AACCAGGTGGACAAGAGGATC-3 -AAGAAGGGCCTGGAGTTCAA-3 -GTTGGCTTACTCATTCACGCA-3 -GCAACCGATTATAAAGTCGTGACC-3 -AAGGAGGTGCTCGATTCGTTC-3 -TGTGGGCCTTTTCGTTAACC-3 -AGCATTTTTCAGACGGCTGG-3 -CAATGCTGTGTTCTATTACTCAACAGG-3 -GGCTTCGTGGCATTTTTTG-3 -TCATTGTCTTCGCCGTGATC-3 -GAGCGACACGCAACATTCA-3 -TCCGCTTTCTGCATCTTCAGT-3 -TCATCGCCTCTTTCTGCAGT-3 -AAGAGCCTTCGCCTTCTGC-3 -CTCTATGTCCCTTTCCTTGGTGT-3 -GTCGGCAGCAAAACATTCC-3 -TTGCCTGAAAGCCCTCGAT-3 -CACGGTCACACAATACTCGGA-3 -TGGAGTTTGTCTCAGGCAAGG-3 -TCTTTGACCGCATCTTGCTTC-3 -GCACTTGGTGCGGAAGAATG-3 -CAAGGACAGTGGCTTCTTTCC-3 -GATGCCCTAGTAGGCGTGGA-3 -TCCTGGTGGGCGAAGTAGA-3 -CCTGCGAGCTTGTATTGGACT-3 -ACCCCAGCGATTTCTTGGA-3 ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? 5 SLC2A14 (NM W 030777)030807)145176) 5 052885) 5 5 5 080282)173076) 5 5 033450)032583)145187) 5 5 5 012089) 5 004170)004171)004172)003038) 5 005628) 5 006516) 5 000340) 5 006931) 5 5 001042) 5 003039)207420)014580) 5 020041) 5 5 5 5 000341)002394)000342)003040) 5 201574) 5 003759) 5 003615) 5 004858) 5 031467) 5 5 5 5 – – – – 001002) 5 001089)018672)080284) 5 080283) 5 5 5 005164)005050)022169)022436) 5 022437) 5 5 5 5 005845)000492)000352) 5 5 5 178559)019625) 5 5 – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – 000291) 5 – – – 003194) 5 – mRNA (GenBank No.) Forward primer (Position) Reverse primer (Position) Probe (Position) SLC4A8 (NM SLC3A2 (NM SLC transporters SLC1A1 (NM ABCD2 (NM SLC2A8 (NM ABCA6 (NM SLC1A5 (NM ABCC10 (NM ABCA7 (AF250238) 5 SLC2A11 (NM ABCG4 (NM SLC2A2 (NM ABCC7 (NM SLC1A3 (NM SLC2A5 (NM SLC4A7 (NM SLC4A9 (NM ABC transporters ABCA3 (NM SLC2A1 (NM SLC2A4 (NM SLC2A13 (NM SLC1A4 (NM ABCA10 (NM ABCB9 (NM ABCB10 (NM SLC4A2 (NM ABCB5 (NM ABCC4 (NM SLC1A2 (NM ABCC12 (NM ABCA5 (NM SLC2A10 (NM ABCA9 (NM ABCG5 (NM ABCC11 (NM SLC4A1 (NM ABCG8 (NM ABCA12 (NM TBP (NM ABCD4 (NM SLC3A1 (NM SLC2A12 (NM SLC2A7 (NM RPLPO (NM SLC2A9 (NM ABCC8 (NM SLC2A3 (NM SLC4A4 (NM SLC4A3 (NM Housekeeping genes PGK1 (NM 458 Masuhiro NISHIMURA and Shinsaku NAITO (1716–1752) continued ? (1128–1160) (649–681) (1134–1166) ? (1084–1115) ? ? (864–894) (739–770) (322–352) ? (693–723) ? (1260–1290) (987–1017) ? (847–876) (506–535) ? (549–578) (1093–1122) (575–605) (1197–1226) ? ? ? ? (1551–1580) ? (1070–1098) ? ? ? (1159–1187) ? (309–336) (2074–2101) (349–376) ? (251–278) ? (1163–1190) ? (334–361) (1391–1418) (126–153) (1018–1045) (667–694) (811–838) (624–650) ? ? (1310–1336) ? ? ? ? (1178–1203) (1618–1644) ? ? ? ? ? (2136–2161) (120–145) ? (698–724) ? (1187–1212) (1242–1267) (361–386) (1817–1841) (1403–1428) (1261–1286) ? ? (1410–1435) (135–159) ? ? (1385–1409) ? (600–624) (1270–1294) ? ? ? ? ? ? (1602–1625) (543–566) ? ? ? (437–460) (1481–1504) (592–615) (1465–1488) (1480–1503) ? ? ? ? ? ? ? ? ? -AACTCTATGTATCATACTTGTGGCCACAGATGCTAGT-3 -CCTTGCGCTTTATGCCTTTTTCAACC-3 -CTGGGCTGGCTGTTTGTCCCCATCTATA-3 -CTTGTGGTCCATGTGCAGAACCAACA-3 -TTTGCCTACCGTGCCCCAGAATGT-3 -TTGATGTTGGCTGCACCAACTACGCATAC-3 -CATGAAGGCTGTGGTCTGGACTGATGTGTT-3 -TCCCTGCCCACCAATCTAACCGTT-3 -CAGCTTTCCTTCAGACAAAATGCTTCGGAC-3 -AAGGTCTCTGTCTTGGATTTCCCAAGGAATGAG-3 -CCAAACACCCCAGAAACACGCCTT-3 -ACAGCTGTGACATGACCCCAAAGCA-3 -AAGGCAAATGAGCTTTGGCCCTGTC-3 -TCTTGACCCTCCTGGACACCTTTGCT-3 -TCTGCGTCACCAACGGTGGCATCTA-3 -ATGTGTCTGAGGTGGCCAAAGACGCA-3 -CTTCGTCATCTTCTCCGTTATCGGCTTCAT-3 -TCTGGTATCGGCTATGCCTCCGTTGT-3 -CCAGTTTGCTTTTCTGGAGACCATTGTGAC-3 -TGCTGCCCTGGGCCTACTGCAATA-3 -TGGCACTCTCCTGGCTTACTCGTTGG-3 -CTACTCTCTGGTGGCAGCCTGTGTTCTCATC-3 -ACCGTGGTCTCTGGCATTATTGCAGCATT-3 -TTATTTCAGATCCCCATGGTTCCCCTG-3 -TACGCCTACATGCTGGAGGTCTACGGCT-3 -CGTAGCGCTCATTGCCATCATTGTC-3 -CCGATTGTCTTCTGCCTCTGCACCAT-3 -AGTTAATGGGTCTCTCTTCACCTCCTCTCGG-3 -CATCATTGGCTCTGGGATCTTCGTTTCC-3 -CTTCTCATCCCCGTGGCGTACTTGG-3 -CAGCTGTGGGCATAACTGTAGTGATGGTCC-3 -TCAAGAGATACTTTGGCTCCACGGTTGC-3 -ATTGCCACCTCCTCCCTGATGCCTTTTA-3 -TCCACCATCGTTCAGCTCTCCTTCACTC-3 -TCCTCTACCTGCTCCTGCCTCTTATCTTTGT-3 -ATGACCGGCACTATGTTAGGACCTGAACTG-3 -TTCCACAGTCCAAGGCCAATTTAGCTTC-3 -TTCGATGCTGTGCTGTACCCTCTCATTG-3 -TGCTGACTCGTGGTTGGGAAAATTCAAG-3 -CTTTACTGCTGCGGTGCAAGCTGCTT-3 -TCGGCCTTGCTTTTGTGGTCTTCCTCT-3 -TTTGGCTTTCTGATTTGTGCAGGAGTTAACGT-3 -TACGTAGAGCAACAGTATGGTCAGCCTTCATC-3 -CCTGCCCATTGGACGGCTTTAACC-3 -CCTGGGCTCTTTCTGTACCAAAATCTACGTG-3 -CTGTCGGAGTCTTCAGATGGCCTGGAAA-3 -ACCAAAGTACATTGAGCAGCAGTATGGACAGTC-3 -CTGCATGCTCTGGCAACAGGAATGTG-3 -ATCTTGGCGTCCACATCTGTTCCTCAAT-3 -CTAGGAACAGAAATTCTTGGCAAGTCAGTTCGT-3 -ACTGAATGTGGAGTGGATGCCCATTCA-3 -ATCACCCGCACCCTTACTGGCTCA-3 -ATTGTGACAGAGTGGGACTTGGTGTGCAACT-3 -TTTTGGCAACACTGGGCTTAGGAGCGT-3 -ACCAGACCAAGCACTTCAGGAGCTCAGAAAG-3 -TCAGATGGCTGTGATGGGTACGGC-3 ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? (1785–1761) 5 (1141–1117) 5 (411–388) 5 ? ? ? (398–376) 5 (602–581) 5 (1324–1304) 5 (2151–2130) 5 (1504–1484)? 5 (1577–1557) 5 (1310–1290) 5 (1359–1338) 5 (885–865) 5 (638–618) 5 (1686–1666) 5 (317–297) 5 (1510–1490) 5 (186–166) 5 (377–357) 5 (725–705)(393–373) 5 5 (900–880) 5 (686–666) 5 (602–582) 5 (1229–1209) 5 (749–729) 5 (1518–1498) 5 (1198–1178) 5 (177–157) 5 (1268–1248) 5 ? ? ? (1624–1604) 5 ? (2209–2190) 5 (715–696) 5 ? ? ? (227–208) 5 (1255–1236) 5 (920–900) 5 ? ? (563–544)? 5 ? (813–794) 5 ? (440–421) 5 ? ? ? ? (1202–1183) 5 ? ? (745–726) 5 (1334–1315) 5 ? ? ? ? ? (1317–1298) 5 (639–620) 5 (1598–1579) 5 ? (1862–1843) 5 ? (1148–1129) 5 (1458–1440)(1249–1230) 5 5 ? ? (1157–1139) 5 (1653–1635) 5 ? ? ? ? (1247–1229) 5 ? ? (682–664) 5 ? ? ? (1084–1066) 5 ? (1201–1183) 5 (1520–1502) 5 ? ? ? (649–631) 5 ? ? ? ? ? ? ? ? ? ? ? ? -TTCAGTAAACCGAGTGATGTAGCAG-3 -ACGTGATGGAAATGAAGAGGG-3 -CTCAGGTACTCTGGCATTGTCAC-3 -ATGTTGCTGGCGAAGAGAGA-3 -GATGAAGCCCGGCCTATTATC-3 -ATGACCGAAAGCATCAGGC-3 -CCACTTAGCATCACCACGACCT-3 -GACAAGGAATAGAACCGCTGC-3 -TTTTCGTCAGCAAGGCCAT-3 -CCATTCCAATACACAGGGCTC-3 -GGCATTGAAGCCACAGACA-3 -ATGGCCTTCACCACTTTGGA-3 -CATGAAGCTGGCTGTCAGAGA-3 -TGCTGGATGTCGTTGCTGA-3 -AAAGAGGATGGACGTGCCG-3 -TGTTGGCTATCGCTTCTGCA-3 -CTTGGTCTGCCACATTCTCAA-3 -GTAGACATTCAGGAGGGACACAAT-3 -TTCTTGGGCCGCAGGTAGTAT-3 -TTGAGCAGGTGGGAGAGGTT-3 -CAGGTTAGGCTGCTCTGGCT-3 -GAACATTTGGGCTGGTCGTA-3 -AGCAGGGTCCCAATTGACA-3 -CAGCATGAGGCAGATGTTGAG-3 -ATGTACTGCGATGAAGGCCG-3 -CCTCAAAGGCGTCCTGAAA-3 -TAAAGTGGAACAGCCACCAGG-3 -AGCGCTTCACGTGGATCAT-3 -CGTGTTGCTGAGCACAGACTT-3 -AGCTGAAGACCAGCAGGAAGG-3 -GCTGTGAGCTTGCAAAAGGTT-3 -CCTGACCCCAGAAACAAGGAT-3 -CATAACCCAGCAGAAAGCCA-3 -AATGCTGTAGATGAGCGGGAA-3 -GAGTTCCACTTTGCACCCAA-3 -AACAGCTGCAGGGATACTTGC-3 -TCACATCCAGAACACATGGCT-3 -TCGATTTCCACCTGCACGAT-3 -ACATGGCCAAGCACATACACC-3 -AACCAAAGAACATCCCCAGC-3 -TTGGTGATGAAAACGCTCTGG-3 -TGGAAGTGTGTTGGGCAAAA-3 -TGACTCCCAATAAGATGTTAGCCTT-3 -TGGCTGTTGTCCAGAGCATC-3 -TTGTGTCAATGAAGACCGCA-3 -CTGGCTATCTGTGGCACTGTCA-3 -GGAATGTTGATGAGCCCGAT-3 -CAAAACGAAACGACGTCACG-3 -CAAGTACGCCGAAAACCATCA-3 -CCAACTGCAAAAAATGTGCAC-3 -ACATAGCCAATCAAGGTGCCC-3 -ATGATGGTAAAACCAGCCAGG-3 -TGCCATGAAGATAGACTGGGC-3 -AGCAAGGGTATTGGCAAGAGC-3 -TCCTTGTGGCCATTTATCCTG-3 -TGTTCATCATGACGCCTGC-3 ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? (1671–1699) 5 ? (1049–1075) 5 ? (1109–1132) 5 (2048–2071) 5 (623–646) 5 (1173–1195) 5 ? ? ? (1785–1806) 5 (520–541) 5 ? (1596–1616) 5 (1155–1175) 5 ? (789–809) 5 (1047–1067) 5 (290–310) 5 (1570–1590) 5 (222–242) 5 (842–862) 5 (578–598)(473–493) 5 5 (1373–1393) 5 (521–541) 5 (339–359) 5 (709–729)(657–677) 5 (563–583) 5 5 (1388–1408) 5 (108–128) 5 (1219–1239) 5 (1364–1384) 5 (643–663)(283–303) 5 5 (1100–1120) 5 ? (1458–1478) 5 (675–695) 5 (1138–1158) 5 (824–844) 5 ? ? ? ? (2115–2134)? 5 ? ? ? (1454–1473) 5 ? ? (1070–1089) 5 ? ? ? ? ? ? (1437–1456) 5 (1238–1257) 5 (597–616) 5 ? ? ? ? ? ? ? ? (415–434) 5 ? ? (1250–1268) 5 ? (1287–1305) 5 (1166–1184) 5 (1137–1155) 5 ? (555–573) 5 ? ? (106–124) 5 (1530–1548) 5 (998–1016) 5 (100–118) 5 ? ? ? (1352–1370) 5 (1238–1256) 5 (312–330) 5 (952–970) 5 ? ? ? ? ? ? ? ? ? ? ? ? ? ? (331–347) 5 ? -GCTGTCATACCTATCTTTAAGAGCTAGCA-3 -CGGGCCTGTGGAATAGTTTCT-3 -TGCCCTGGTTTTGGTGGTT-3 -CTGCTGGTCATTGGCGTTG-3 -TCTTGGAGCAGTCCGTTTGA-3 -TGAATGCGTGAAACACTGTGG-3 -ATCTGCACCTTCTACACGGCTG-3 -TCCCTCTAATGGGTCCAGCTT-3 -CCATGTTTGCACGGAACATC-3 -AACCTTACTTCAGATCGCTCTCAG-3 -GATGTGCCCTTGGGAACTAAA-3 -CGAGATGGTTCAAGAAAACACG-3 -AACTTCCCGAGAGTTCCTGGT-3 -TGTTCTGCATAACCAAGGGTG-3 -TCATCGTCCTGGCGACCTT-3 -CATGGCTGAGATGAGGAATGA-3 -TGCCACAAGCATCTTTGCC-3 -GGAAAAGATCTGCCCCTTGTT-3 -GCTTCTGACTCTCGGCCTAGATA-3 -TTCTTCTCGTCCATGACGCA-3 -GACTTGGTGGACCTCATGTCC-3 -TGTCCATTGGCACACTCATG-3 -CACACGCACCCCAATCATA-3 -CCAGCAACAGTATCGGGAAGA-3 -TCCAAATCGGGCGGAGA-3 -ACACGTTCACTTACGCCAAGG-3 -CCCTCAAGCTCAGCGTTTT-3 -ATGCCCATTTCTGTTGCCC-3 -ATCTCCATCATCGTGGGCA-3 -ACAGGCCCATCAAGGTGAA-3 -GTGAAATCCCTGAACTTGCGA-3 -CCCATGCAGTGGAGCTCAATA-3 -ATGTTTGCCATGACACCACTC-3 -GATGCAGAACACGCAGCTATG-3 -CCACTTCTCGGAAAACCCA-3 -TGACTCTGGTGGTCCTTTTCA-3 -GCTCTTGCCGTTATTCAGCTG-3 -TCGTGATCATGGTCCCGAT-3 -TTTACTCCCATCCTGGGAGCA-3 -TGAAGGACCGCTTGATCGA-3 -TTATGCGATCCCCACTGTCTG-3 -ACTGACACTCGTTGGGTCGGT-3 -GCAGCTATATTGGTGCTTTTACTTATG-3 -TGTCTCCAAGCTGCATGGAG-3 -CACGATGCTGGTATTTGGACC-3 -CCATAGCCTGCTTCTTATACAAGC-3 -ATTCTCTGTTCGGCATGGTGA-3 -TGGAGCAGTCATTGACACCA-3 -CTGAGCTGTACCCCACATTCA-3 -TCTCCAACTATGTGGTAGCCTTCA-3 -GGCTGGCATCTCCCTCAACT-3 -CAGCCTCCGTCAGCTATGTAA-3 -ATGGCTGGGTCTACAACAGCA-3 -AGAAATGCAGACGCTGCGT-3 -GGTGGCTGATTATTAAGGGCA-3 -TGGTGCTAACCTGGAGCTACC-3 ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? 013272)016354)017435) 5 030958) 5 5 5 018484)144585) 5 5 022058)032034) 5 5 152351)052944)178498) 5 5 5 019849)014331)138817) 5 003049) 5 000452) 5 019848) 5 152679) 5 001010893) 5 005073) 5 5 021082)016582) 5 145648) 5 134431) 5 006446) 5 007256) 5 5 5 003058)003059) 5 006672) 5 004254)080866) 5 5 5 – – – – – – 000343)003041)006933)014227) 5 000453) 5 021095) 5 021815) 5 145913) 5 5 5 5 001043)001044)001045)004211) 5 003043) 5 014228) 5 006934) 5 003045) 5 003046) 5 032803) 5 004173) 5 003486) 5 003983) 5 003982) 5 012244) 5 014270) 5 5 5 5 – – – – – – – – – – – – – – – – – – – – – – – – – (continued) – – – – – – – – – – – – – – – – – – – – – – – – mRNA (GenBank No.) Forward primer (Position) Reverse primer (Position) Probe (Position) SLC7A4 (NM SLC21A9 (NM SLC22A9 (NM SLC5A1 (NM SLC21A15 (NM SLC5A2 (NM SLC5A3 (NM SLC21A3 (NM SLC22A12 (NM SLC10A5 (NM SLC15A1 (NM SLC7A13 (NM SLC6A2 (NM SLC7A1 (NM SLC6A4 (NM SLC4A11 (NM SLC7A2 (NM SLC10A2 (NM SLC10A3 (NM SLC7A11 (NM SLC15A3 (NM SLC21A14 (NM SLC15A4 (NM SLC5A5 (NM SLC5A6 (NM SLC5A8 (NM SLC22A4 (NM SLC10A4 (NM SLC21A11 (NM SLC22A8 (NM SLC7A10 (NM SLC15A2 (NM SLC22A2 (NM SLC22A7 (NM SLC5A10 (NM SLC7A7 (NM SLC7A6 (NM SLC21A6 (NM SLC6A7 (NM SLC6A6 (NM SLC5A12 (NM SLC6A3 (NM SLC7A8 (NM SLC6A5 (NM SLC7A5 (NM SLC5A4 (NM SLC5A7 (NM SLC6A9 (NM SLC22A6 (AF124373) 5 SLC21A12 (NM SLC7A3 (NM SLC7A9 (NM SLC10A1 (NM SLC22A11 (NM SLC5A11 (NM Table 3. SLC4A10 (NM mRNA Expression Proˆles of Human Drug Transporters 459

of the TaqMan probe. In order to prepare the transporter calibration curves, the total RNA obtained from the tissue exhibiting the highest mRNA expression levels was used for the individual transporter isoforms. When (1214–1246)

? preparing the calibration curves, various amounts (526–555) (439–468) (322–351) (553–582) ? ? ? (1426–1454) ? (1321–1349) (925–953) ranging from 1.28 to 100,000 pg of total RNA were (1129–1156) ? (652–679) ? (606–633) (1239–1266) (427–453) ? (418–445) (738–764) ? (555–581) ? ? ? ? ? ? (1057–1082) (921–946)

? used. The lower limit of quantiˆcation for each mRNA ? ? (887–910) (789–813) (1710–1733) (188–211) (1398–1421) ? ? ? ? ranged between 1.28 and 4000 pg of total RNA per 50 ? mL of reaction mixture. The upper limit of quantiˆca- tion for each mRNA was higher than 100,000 pg of total RNA per 50 mL of reaction mixture. The relative amounts of housekeeping gene mRNAs in each tissue used in this study are shown in Table 4. Data are expressed as the ratio to the lowest value for each housekeeping gene. For example, the expression of b-actin mRNA was 41.9-fold higher in peripheral leukocytes than in the pancreas, and the expression of -CCTTGTGATATGGGCTGGGAATATCCTGAG-3 -CTCTGCAAGGTGACCTTGGTGATGAGCT-3 -CCGCTGCTAGAAACATTCTCCGACCTTCA-3 -CAGTGGAACCTGGTCTGTGACCGAAAA-3 -CTTATCCTGGGCTTCACCAACTTCATTGC-3 -CTGATCAAGGCTGTCTCCACCTCGGA-3 -TGATGCAAGTCACCATGGGCACCA-3 -TATCCTCTTTGCCTGCTCCAAACACCA-3 -AATCGTGATCGGCGGACTCACATC-3 -TTGACCATCATCTGTTACCTGGGCCTGC-3 -CATCCTCATGTCCATCGTGTGTTACCTG-3 -TGTTCTTGCGGCCCATGTGTTTTCT-3 -TACCTCTTAGCCTTGGGCCCTCTCCTTT-3 -ACCACCAATAACTGCCACAACAATGAGACG-3 -TTCCCTATACATTGGCATGGCGGCTC-3 -TTCCCCTGGCCATAAAGAATGCCG-3 -CATTGTGATTTCCTTCGTTGGAGCTGTG-3 -ACTTGTTGGTGATCTTCATACCCTCCATGAAGG-3 -AAGCTTGCAGCATCTGGATCAATTACAATG-3 -CCCCAAAATCCTGGCCCTGTGTTT-3 -CTGTTATTTCCCAAACGACCCTTCAGCTG-3 -CTGTGAGGCCCAGATGTTCACAGTTGA-3 -CTTCCCAAAATAGGCTTTCTTGGCTACACA-3 ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? GAPDH mRNA was 108-fold higher in skeletal muscle than in the pancreas. Consistent with the ˆndings of our previous studies,15,16) the expression of PPIA mRNA (1281–1255) 5

(510–485) 5 showed the lowest variability among the housekeeping ? ? (1183–1161) 5 (297–275) 5 genes studied. The expression of GUSB, PGK1, and (1423–1401) 5 (758–736) 5 (882–861) 5 ? ? ? ? (1444–1424) 5 (1123–1103)(986–966) 5 5 ? (1476–1456) 5 (621–601) 5 (465–445) 5 (646–626) 5 (1001–981) 5 (377–357) 5 (1766–1746) 5 (822–803) 5

? RPLPO mRNA also showed low variability among the ? ? (656–637) 5 ? ? ? ? ? ? ? ? (974–956) 5 ? (473–455) 5 (1289–1271) 5 (694–676) 5 ? ? ?

? housekeeping genes studied. Therefore, in the present study, we considered GUSB, PGK1, PPIA, and RPLPO mRNA to be suitable as endogenous controls for the measurement of transporter mRNAs, and we then selected PPIA, which showed the lowest variability and was used as an endogenous control in our previous studies.15,16) The process used to select the best housekeeping gene has been described in detail in our previous

-TCATTCTTCAGGGATGGGAGC-3 -AGGTGTAACTGACGGTAAACCAC-3 -CAGCCTGCGATACGAATACAC-3 -TGGATCAGCATTGCAAGCC-3 -TAGCAGTGGCGAATGGCAT-3 -GTGGTTGTACAGAGGCGCAGA-3 -TAGGGCCGGATCAGTAATGGA-3 -ACCTAGGCCCGAAAACACTGT-3 -GAGGCGATATCACGCTTTCTG-3 -ATGAGGTCCAACTTGGTCTCCTG-3 -CTTGGGCCTGGGATGATTT-3 -GTGGGAATCAATGAATCTGGAG-3 -CACGTCGCAGATGCTGATAAA-3 -CTCGGAGGTTCCTGATGAAAA-3 -GGCAGGTTAAGGCTTATGCTG-3 -GTGTTGAGCACAGTTCAACAGGA-3 -ATTAGGGCCAATGTGCTGC-3 -GTTAGCAGATGTAACTCCTACGACTCC-3 -TTTCACTATGAAGAGGTAGCTTGACA-3 -TCAGCAAGAAGCCAAGCATAG-3 -TTATAGTTGGCACAAGGATGACC-3 -CTCAGGGTGGCAGACAAAAG-3 -GGACAAGGGATGGACCATTT-3 16,22) ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? studies. The mRNA expression levels of 46 human ABC transporters in various tissues are shown in Table 5.ABCA1 mRNA was found to be widely expressed in adult tissues, with the highest level of expression in the adrenal gland. The results for ABCA1 were similar to (411–435) 5

(764–787) 5 23–26) 27) (1104–1127) 5 ? (581–604) 5 (1179–1202) 5

? those reported in human subjects and the mouse. ? (1296–1318) 5 ? ? ? (612–633) 5 (365–385) 5 (863–883) 5 (1401–1421) 5 (533–553) 5 (530–550) 5 ? Consistent with the ˆndings of other studies in human (903–922) 5 ? ? ? (900–919) 5 ? (405–423) 5 (506–524)(1378–1396) 5 5 ? (1036–1054) 5 (159–177)(715–733) 5 5 (298–316)? 5 (1689–1707) 5 (1205–1223) 5 28) 27) 29) ? ? ? ? ? ? ? ? ?

? subjects, the mouse, and the rat, ABCA2 mRNA was expressed at high levels in the brain and spinal cord. Consistent with the ˆndings of other studies in human subjects,30–32) ABCA3 mRNA levels were the highest in the lung. ABCA3 mRNA was also expressed at high levels in the brain and spinal cord, with low levels of expression in other tissues. ABCA4 mRNA showed no or very weak expression in many tissues. Consistent with

-AGCCACCGCTTCAATGAGA-3 -CCTGGACTTCTGTAAGAATAGGCA-3 -GTTATTGCCGGAGACCCTTAA-3 -ATGGAAAAGCACTGCGGTG-3 -CCGCAACATCTGGAAAAATC-3 -AACGTGGTCACCGACAGCA-3 -GGGTGATCCTGAAGATTGCCT-3 -CAGGAATCTGCATGTTCATCC-3 -TGCCAATATCGGGTCCCTA-3 -TGCCTTCGGCTACTTTATCACA-3 -GGTACTTTATCACGCCCTATGTGG-3 -AGTATGCCAGGTACTACATGAGGC-3 -TGAACAACGTCCTGGTGGAGA-3 -TGATAGAAGCGGCCAATGG-3 -TTTGGGAATGTCCATCGTCA-3 -ATGCAACATTGGCACAGGG-3 -CTTGTGCCGGAGCAATTCT-3 -TACCGTGGTTACCTGCATACTCTT-3 -GGGATATAAGGCATTTGGATTAGTT-3 -AAGGAGCCTGCAAGATCCA-3 -CCCAATTCGTACATCAGTGATCA-3 -CCCAGCCAAGGACTCAACA-3 -GCATTGTGTTCCCTCTTGCAC-3 30,33,34) ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? the ˆndings of other studies in human subjects, ABCA5 mRNA and ABCA6 mRNA were expressed ubiquitously and were expressed at the highest levels in skeletal muscle and the liver, respectively. Consistent 004256)004803)018420) 5 033125) 5 020372) 5 002555) 5 5 5 004213)004212)022127) 5 004955) 5 001532) 5 018344) 5 153247) 5 078483) 5 181776) 5 181774) 5 152313) 5 030674) 5 018976) 5 006841) 5 018018) 5 033518) 5 153811) 5 5 5 – – – – – – 24) – – – – – – – – – – – – – – – – –

(continued) with the ˆndings of another study in human subjects, ABCA7 mRNA was expressed at high levels in the bone marrow, peripheral leukocytes, spleen, and thymus. mRNA (GenBank No.) Forward primer (Position) Reverse primer (Position) Probe (Position) SLC28A1 (NM SLC29A2 (NM SLC38A5 (NM SLC38A2 (NM SLC29A4 (NM SLC38A3 (NM SLC29A1 (NM SLC22A14 (NM SLC36A4 (NM SLC22A17 (NM SLC28A3 (NM SLC22A18 (NM SLC36A3 (NM SLC29A3 (NM SLC38A1 (NM SLC22A15 (NM SLC22A16 (NM SLC38A4 (NM SLC36A2 (NM SLC36A1 (NM SLC38A6 (NM SLC28A2 (NM Table 3. SLC22A13 (NM The positions of the primers and probes were counted fromHowever, the position of the initiation codon. in the rat, ABCA7 mRNA was not expressed 460 Masuhiro NISHIMURA and Shinsaku NAITO

Table 4. Relative Amounts of Human Housekeeping Gene mRNAs in Various Tissues

Tissue b-actin B2M GAPDH GUSB HPRT1 PGK1 PPIA RPLPO TBP TFRC Adrenal gland 16.0 10.8 6.59 6.39 6.13 8.14 5.82 4.10 7.41 8.25 Bone marrow 24.2 6.04 6.84 6.61 6.08 3.26 3.02 1.99 4.86 52.7 Brain 20.0 1.53 13.6 2.81 23.8 9.78 9.42 1.00 6.89 10.8 Colon 31.6 15.4 12.9 7.75 8.75 5.72 6.94 12.09 5.56 30.5 Heart 4.42 6.28 28.3 2.96 5.28 11.6 3.42 2.23 5.13 6.28 Kidney 11.1 4.39 17.1 6.63 5.50 9.42 5.19 1.94 5.08 5.37 Liver 3.36 3.42 3.78 6.43 1.80 1.78 2.20 1.43 1.00 1.10 Lung 24.6 25.8 4.84 8.43 5.26 6.89 6.84 3.14 7.29 17.6 Pancreas 1.00 1.00 1.00 2.06 2.38 1.00 2.31 5.74 1.44 1.00 Peripheral leukocytes 41.9 35.6 7.89 10.0 5.33 6.75 5.43 5.13 4.35 6.92 Placenta 12.3 2.86 3.82 11.6 1.00 3.61 2.06 1.88 5.56 34.3 Prostate 15.4 10.8 6.73 6.92 4.86 5.15 4.96 4.45 7.52 7.11 Salivary gland 5.26 3.75 3.31 3.28 1.31 2.16 1.94 2.84 2.39 1.29 Skeletal muscle 2.99 1.81 108 1.00 2.03 8.97 1.00 4.29 3.45 6.99 Small intestine 33.2 11.3 11.6 7.11 6.94 4.84 5.74 4.10 4.48 10.2 Spinal cord 23.3 3.77 18.0 2.80 6.59 6.45 5.35 1.42 4.89 6.43 Spleen 26.4 21.6 3.27 4.92 3.08 3.69 3.47 2.33 4.47 3.00 Stomach 24.8 7.78 7.11 4.32 4.59 3.53 4.48 3.47 4.01 7.44 Testis 10.6 1.47 7.67 9.29 33.4 2.07 3.59 2.74 50.4 7.65 Thymus 29.8 9.65 9.95 6.19 6.75 6.39 8.63 3.71 6.99 5.84 Thyroid gland 10.9 6.61 5.72 6.68 5.21 5.01 4.42 3.39 7.39 3.39 Trachea 9.58 8.49 4.55 3.78 2.15 2.83 2.56 2.61 4.71 3.76 Uterus 36.0 5.43 6.23 6.13 3.18 2.82 4.14 3.78 6.06 3.48

Data are expressed as the ratio to the lowest value for each housekeeping gene. Total RNA at 25,000 pg per 50 mLofreactionmixturewasusedfor each tissue. Experiments were performed in duplicate. The highest values of Ct for b-actin, b-2-microglobulin (B2M), glyceraldehyde 3-phosphate dehydrogenase (GAPDH), b-glucuronidase (GUSB), hypoxanthine phosphoribosyltransferase 1 (HPRT1), phosphoglycerate kinase 1 (PGK1), peptidylprolyl isomerase A (PPIA), ribosomal protein large P0 (RPLP0), TATA box binding protein (TBP), and transferrin receptor (TFRC) in various tissues were 22.65, 22.99, 23.04, 27.27, 28.48, 24.81, 23.48, 22.10, 28.33, and 28.17, respectively.

Table 5. Expression of Human ABC Transporter mRNAs in Various Tissues

Tissue ABCA1 ABCA2 ABCA3 ABCA4 ABCA5 ABCA6 ABCA7 ABCA8 ABCA9 ABCA10 ABCA12

Adrenal gland 0.363 0.0402 0.00259 0.000207 0.0689 0.0794 0.00643 0.139 0.0150 0.00826 BLQ Bone marrow 0.0370 0.0190 0.000176 0.00125 0.0487 0.0433 0.0550 0.00510 0.00959 0.00245 BLQ Brain 0.0196 0.311 0.00982 0.000610 0.105 0.0228 0.00840 0.0311 0.00929 0.00882 BLQ Colon 0.0661 0.0280 0.000743 0.000301 0.0573 0.0353 0.00521 0.0319 0.0120 0.00340 BLQ Heart 0.0640 0.0502 0.00120 0.000281 0.129 0.300 0.00308 0.429 0.131 0.0474 BLQ Kidney 0.0180 0.0517 0.00105 0.00809 0.0434 0.0239 0.00478 0.0184 0.00789 0.00558 BLQ Liver 0.124 0.0184 0.0000604 0.000377 0.0497 0.379 0.00195 0.0540 0.0187 0.00486 BLQ Lung 0.171 0.0231 0.0361 0.000544 0.0391 0.184 0.0125 0.0947 0.0430 0.0226 BLQ Pancreas 0.0198 0.0172 0.00105 BLQ 0.0811 0.0330 0.00277 0.00999 0.00739 0.00692 BLQ Peripheral leukocytes 0.0326 0.0448 0.000527 BLQ 0.0150 0.00190 0.0317 BLQ 0.000375 0.000593 BLQ Placenta 0.173 0.0175 0.00116 0.00193 0.0393 0.00554 0.00867 0.00450 0.000413 0.000662 0.000813 Prostate 0.0450 0.0367 0.00222 0.000383 0.0890 0.0402 0.00370 0.0292 0.0110 0.00855 0.0000903 Salivary gland 0.0230 0.0272 0.00145 0.0000881 0.0223 0.0402 0.0137 0.0228 0.0118 0.0106 BLQ Skeletal muscle 0.157 0.0701 0.00188 0.000413 0.543 0.189 0.0118 0.102 0.0557 0.0589 BLQ Small intestine 0.0282 0.0163 0.000748 0.000281 0.0281 0.0234 0.00478 0.0223 0.00537 0.00246 BLQ Spinal cord 0.0921 1.22 0.0153 0.000304 0.0575 0.0925 0.00461 0.101 0.0317 0.00855 BLQ Spleen 0.0851 0.0364 0.000672 0.000274 0.0198 0.0120 0.0208 0.0256 0.00191 0.00156 BLQ Stomach 0.0369 0.0205 0.000421 0.000329 0.0485 0.0518 0.00773 0.0405 0.0143 0.00861 0.000782 Testis 0.0725 0.0437 0.00473 0.00293 0.102 0.0663 0.00260 0.0957 0.0475 0.0302 0.00375 Thymus 0.0822 0.0129 0.00163 0.000233 0.0129 0.0146 0.0286 0.00716 0.00809 0.00326 BLQ Thyroid gland 0.0524 0.108 0.00483 0.00103 0.0881 0.0934 0.00702 0.0686 0.0352 0.0214 BLQ Trachea 0.0608 0.0385 0.00158 0.000295 0.0538 0.121 0.0185 0.0520 0.0394 0.0186 0.00169 Uterus 0.0569 0.0223 0.00112 0.000777 0.0204 0.0713 0.00232 0.0230 0.0329 0.0155 BLQ

Table 5. (continued)

Tissue ABCB1 ABCB2 ABCB3 ABCB4 ABCB5 ABCB6 ABCB7 ABCB8 ABCB9 ABCB10 ABCB11 Adrenal gland 0.297 0.0513 0.0127 0.0110 0.0000180 0.00687 0.00458 0.0569 0.0103 0.0315 BLQ Bone marrow 0.00291 0.0459 0.0181 0.00141 0.000977 0.0133 0.00632 0.0205 0.00439 0.441 BLQ Brain 0.00913 0.00979 0.00763 0.0000887 0.0000178 0.00493 0.00407 0.0442 0.0428 0.0307 BLQ Colon 0.0133 0.0836 0.0179 0.000480 0.000361 0.00319 0.00624 0.0314 0.00592 0.0411 0.000284 Heart 0.00503 0.0373 0.0106 0.0107 0.0000539 0.0120 0.0224 0.0354 0.0123 0.0561 BLQ Kidney 0.0851 0.0256 0.0103 0.000425 0.0000185 0.00600 0.00697 0.0459 0.00936 0.0428 BLQ Liver 0.0230 0.0259 0.00752 0.150 BLQ 0.00992 0.00457 0.0244 0.00124 0.0310 0.163 Lung 0.00789 0.166 0.0470 0.000248 0.0000461 0.00198 0.00469 0.0261 0.00372 0.0386 BLQ Pancreas 0.00171 0.0144 0.00607 0.000187 0.0000279 0.00304 0.00255 0.0151 0.00419 0.0181 BLQ Peripheral leukocytes 0.00907 0.154 0.0472 0.000824 0.0000199 0.000523 0.00721 0.0238 0.00182 0.0450 BLQ Placenta 0.0255 0.0698 0.0115 0.000122 BLQ 0.00643 0.00273 0.157 0.00965 0.0385 BLQ Prostate 0.00814 0.0634 0.0112 0.000669 0.000408 0.0104 0.00664 0.0311 0.0104 0.0415 BLQ Salivary gland 0.00121 0.0348 0.00662 0.000516 0.0000415 0.00498 0.00345 0.0263 0.0140 0.0319 BLQ Skeletal muscle 0.00154 0.0529 0.0175 0.0270 BLQ 0.103 0.0336 0.0775 0.00611 0.158 BLQ Small intestine 0.0337 0.0610 0.0186 0.000614 0.000101 0.00416 0.00607 0.0320 0.0112 0.0538 BLQ Spinal cord 0.0163 0.0475 0.0106 0.000743 0.0000733 0.00867 0.00582 0.0445 0.0268 0.0221 BLQ Spleen 0.00891 0.210 0.0418 0.00870 0.0000162 0.00142 0.00433 0.0217 0.00486 0.0439 BLQ Stomach 0.00313 0.0531 0.0148 0.000883 0.000136 0.00752 0.00460 0.0292 0.00300 0.0322 BLQ Testis 0.00209 0.0693 0.00742 0.00289 0.00498 0.0652 0.00498 0.0925 0.164 0.0401 0.0396 Thymus 0.00127 0.0715 0.0210 0.000284 0.0000522 0.00149 0.00379 0.0238 0.00476 0.0219 0.000361 Thyroid gland 0.00521 0.0261 0.00985 0.000688 0.0000335 0.00812 0.00867 0.0393 0.0115 0.0409 BLQ Trachea 0.00402 0.0703 0.0178 0.000549 0.0000427 0.00657 0.00392 0.0294 0.0103 0.0490 0.000361 Uterus 0.0102 0.0415 0.0130 0.000375 0.000309 0.00721 0.00425 0.0390 0.0135 0.0393 BLQ

Table 5. (continued)

Tissue ABCC1 ABCC2 ABCC3 ABCC4 ABCC5 ABCC6 ABCC7 ABCC8 ABCC9 ABCC10 ABCC11 ABCC12

Adrenal gland 0.0307 0.00106 0.315 0.00823 0.0194 0.000242 0.0000111 0.00726 0.00949 0.0377 0.000222 BLQ Bone marrow 0.0389 0.00169 0.00843 0.0616 0.0327 0.0000828 0.0000039 0.000230 0.00402 0.0217 0.0000417 BLQ Brain 0.00855 0.000408 0.000360 0.0105 0.0484 0.0000275 0.000374 0.0307 0.00809 0.0155 0.000551 BLQ Colon 0.0215 0.000581 0.142 0.0360 0.0125 0.000473 0.0691 0.000780 0.00814 0.0125 0.0000471 BLQ Heart 0.0291 0.000597 0.000750 0.0207 0.0597 0.0000881 0.000883 0.00414 0.203 0.0120 0.000116 BLQ Kidney 0.0141 0.0751 0.0484 0.180 0.0193 0.00873 0.000522 0.000237 0.00724 0.0219 0.000237 BLQ Liver 0.00326 0.208 0.114 0.00294 0.00500 0.00982 0.000853 0.0000349 0.0902 0.00570 0.00381 BLQ Lung 0.0414 0.00119 0.0107 0.110 0.0188 0.00224 0.0185 0.00121 0.0369 0.0226 0.000103 0.000111 Pancreas 0.00776 0.00180 0.0506 0.0126 0.00342 0.000311 0.187 0.0161 0.0104 0.0188 0.000120 0.00155 Peripheral leukocytes 0.0437 0.00208 0.0136 0.0253 0.0145 0.000135 0.0000118 BLQ BLQ 0.0295 0.0000330 BLQ Placenta 0.0224 0.00311 0.0183 0.00942 0.00803 0.0000869 0.000160 0.000197 0.000631 0.0531 0.00104 0.0000432 Prostate 0.0563 0.00142 0.0163 0.493 0.0280 0.000428 0.00580 0.00368 0.0244 0.0265 0.00371 0.000159 Salivary gland 0.00913 0.00104 0.00483 0.0129 0.0106 0.00114 0.0358 0.000126 0.00227 0.0293 0.000212 0.0000327 Skeletal muscle 0.268 0.00514 0.000332 0.0830 0.120 0.00314 0.0000135 0.00264 0.253 0.0354 0.000128 BLQ Small intestine 0.0184 0.0273 0.0513 0.0396 0.00820 0.000960 0.0173 0.000892 0.00680 0.0230 0.000633 0.0000288 Spinal cord 0.0173 0.000877 0.00852 0.0436 0.0267 0.000116 0.000953 0.0144 0.0176 0.0142 0.00180 0.000105 Spleen 0.0480 0.00165 0.0222 0.0223 0.0320 0.0000196 0.000459 0.000153 0.00949 0.0297 0.0000132 BLQ Stomach 0.0447 0.00135 0.103 0.0390 0.0347 0.000440 0.0139 0.000761 0.0239 0.0273 0.0000168 0.00121 Testis 0.133 0.00387 0.00635 0.0713 0.0581 0.0000380 0.0117 0.000551 0.00372 0.0258 0.0302 0.0931 Thymus 0.0494 0.00245 0.00413 0.0149 0.0160 0.0000226 0.0000181 0.0000552 0.00149 0.0266 0.000113 0.0000222 Thyroid gland 0.0365 0.000853 0.00433 0.0587 0.00752 0.000276 0.00160 0.00812 0.0223 0.0194 0.000228 0.0000273 Trachea 0.0691 0.00126 0.0150 0.0520 0.0464 0.000520 0.00236 0.000464 0.00975 0.0379 0.000148 BLQ Uterus 0.0338 0.000927 0.00936 0.0360 0.0181 0.0000287 0.000499 0.00422 0.0285 0.0223 0.0000762 0.0000072

BLQ, below the limit of quantiˆcation. Data are expressed as the ratio of the target mRNA to PPIA mRNA. Experiments were performed in duplicate. The highest values among the various tissues are shown in boxes. or was expressed at lower levels in the bone marrow, expressed ubiquitously. Consistent with the ˆndings of peripheral leukocytes, spleen, and thymus.35) Consistent another study in human subjects,39) ABCA12 mRNA with the ˆndings of another study in human subjects,36) showed no or very weak expression in all of the tissues ABCA8 mRNA was expressed at the highest levels in the analyzed in the present study. heart. Similar to the ˆndings of other studies in human ABCB1 mRNA was expressed at the highest levels in subjects,37,38) ABCA9 mRNA and ABCA10 mRNA were the adrenal gland. Consistent with the ˆndings of 462 Masuhiro NISHIMURA and Shinsaku NAITO

Table 5. (continued)

Tissue ABCD1 ABCD2 ABCD3 ABCD4 ABCE1 ABCF1 ABCF2 ABCG1 ABCG2 ABCG4 ABCG5 ABCG8

Adrenal gland 0.183 0.00904 0.0693 0.00985 0.0563 0.101 0.105 0.113 0.0117 0.000434 0.000234 0.000415 Bone marrow 0.0254 0.0179 0.0822 0.00483 0.0723 0.0957 0.0746 0.0117 0.0104 0.000360 0.0000320 0.0000159 Brain 0.00834 0.0736 0.0634 0.00436 0.0614 0.0715 0.0896 0.0204 0.0224 0.0173 0.0000520 0.000807 Colon 0.0411 0.00975 0.162 0.00697 0.0433 0.116 0.0559 0.0205 0.00784 0.000296 0.000143 0.000681 Heart 0.0836 0.0728 0.202 0.0106 0.137 0.173 0.209 0.0350 0.00541 0.00177 0.0000680 0.000116 Kidney 0.0307 0.00271 0.258 0.0184 0.0529 0.118 0.122 0.0190 0.00463 0.000402 0.0000834 0.000607 Liver 0.0292 0.000328 0.115 0.0112 0.0260 0.0645 0.0249 0.00602 0.0139 0.000176 0.128 0.234 Lung 0.0368 0.00452 0.0805 0.00596 0.0577 0.143 0.0887 0.0619 0.0106 0.000182 BLQ 0.0000964 Pancreas 0.0310 0.000538 0.0713 0.00678 0.0682 0.0921 0.0649 0.00264 0.000267 0.0000577 BLQ BLQ Peripheral leukocytes 0.0730 0.0301 0.0170 0.00724 0.0524 0.0808 0.0600 0.0201 0.000264 0.0000256 BLQ BLQ Placenta 0.318 0.000107 0.0533 0.0149 0.0338 0.296 0.135 0.0931 0.0954 0.000216 BLQ BLQ Prostate 0.0374 0.00339 0.113 0.00752 0.0851 0.115 0.109 0.0244 0.0147 0.000516 BLQ BLQ Salivary gland 0.0356 0.00709 0.0520 0.00657 0.0386 0.0951 0.0811 0.0295 0.00855 0.000108 0.0000299 0.0000411 Skeletal muscle 0.475 0.00350 0.296 0.0161 0.150 0.983 0.714 0.0902 0.00163 0.000850 BLQ 0.0000851 Small intestine 0.137 0.00496 0.130 0.00789 0.0389 0.0890 0.0561 0.0110 0.0492 0.000499 0.0619 0.0540 Spinal cord 0.0242 0.0275 0.117 0.0138 0.0645 0.0954 0.124 0.0225 0.0355 0.00781 0.000188 0.000405 Spleen 0.0597 0.0126 0.0451 0.00809 0.0593 0.115 0.109 0.0854 0.00288 0.000222 0.0000133 0.0000115 Stomach 0.0291 0.00913 0.134 0.00468 0.0711 0.118 0.0730 0.0143 0.00199 0.000382 0.000627 0.000780 Testis 0.292 0.00384 0.107 0.0147 0.145 0.358 0.357 0.00742 0.0113 0.0333 0.000157 0.000555 Thymus 0.0402 0.00478 0.0652 0.00562 0.0196 0.0974 0.0583 0.0422 0.000899 0.00515 BLQ 0.0000083 Thyroid gland 0.0329 0.00238 0.0918 0.0135 0.0842 0.117 0.0938 0.0230 0.00834 0.000877 0.0000159 0.0000102 Trachea 0.0331 0.00817 0.101 0.00765 0.0518 0.134 0.105 0.0550 0.00413 0.000409 0.0000244 0.0000496 Uterus 0.0679 0.0164 0.0571 0.00904 0.0400 0.140 0.0947 0.0174 0.0492 0.00101 0.0000268 0.0000408

another study in the rat,40) ABCB1 mRNA was also Consistent with the ˆndings of other studies in the rat50) expressed at high levels in the small intestine. Similar to and the mouse,51) ABCC6 mRNA was expressed at high the ˆndings of another study in the rat,41) ABCB2 levels in the liver. ABCC7 mRNA and ABCC8 mRNA mRNA and ABCB3 mRNA were expressed ubiquitous- were expressed at the highest levels in the pancreas and ly. Consistent with the ˆndings of another study in brain, respectively. Consistent with the ˆndings of human subjects,42) ABCB4 mRNA was expressed at the another study52) in human subjects, the mouse, and the highest levels in the liver. ABCB5 mRNA was expressed rat, ABCC9 mRNA was expressed at very high levels in at high levels in the testis, with no or very weak expres- the heart and skeletal muscle. ABCC10 mRNA was sion in other tissues. Consistent with the ˆndings of expressed ubiquitously. ABCC11 mRNA was expressed another study in the rat,43) ABCB6 mRNA was also at the highest levels in the testis, with very weak expres- expressed ubiquitously. ABCB7 mRNA and ABCB8 sion in other tissues. Consistent with the ˆndings of mRNA were also expressed ubiquitously. Similar to the another study in the rat,53) ABCC12 mRNA was also ˆndings of other studies in human subjects,44,45) ABCB9 expressed at the highest levels in the testis, with no or mRNA and ABCB10 mRNA were expressed ubiqui- very weak expression in other tissues. tously and were expressed at the highest levels in the Similar to the ˆndings of another study in human testis and bone marrow, respectively. Consistent with subjects,54) ABCD1 mRNA was expressed ubiquitously. the ˆndings of another study in the rat,46) ABCB11 ABCD2 mRNA was also expressed ubiquitously. mRNA was expressed at the highest levels in the liver, However, consistent with the ˆndings of another study with no or very weak expression in other tissues. in human subjects,55) ABCD2 mRNA was found at high Similar to the ˆndings of another study in the rat,47) levels in the brain and heart, with weak expression in ABCC1 mRNA was widely expressed in many tissues, skeletal muscle. ABCD3 mRNA was expressed ubiqui- andABCC2mRNAwasexpressedathighlevelsinthe tously. Similar to the ˆndings of other studies in human kidney, liver, and small intestine. ABCC3 mRNA was subjects,56,57) ABCD4 mRNA was expressed ubiqui- expressed at the highest levels in the adrenal gland. tously. Consistent with the ˆndings of other studies in human Consistent with the ˆndings of another study in subjects30) and the mouse,48) ABCC3 mRNA was also human subjects,58) ABCE1 mRNA was expressed expressed at high levels in the colon, liver, pancreas, ubiquitously and was expressed at high levels in the small intestine, and stomach. However, in the rat, heart, skeletal muscle, and testis. ABCC3 mRNA was expressed at very low levels in the Consistent with the ˆndings of another study in liver.47,49) ABCC4 mRNA and ABCC5 mRNA were human subjects,59) ABCF1 mRNA was expressed expressed ubiquitously and were expressed at the highest ubiquitously and was expressed at the highest levels in levels in the prostate and skeletal muscle, respectively. skeletal muscle. ABCF2 mRNA was also expressed mRNA Expression Proˆles of Human Drug Transporters 463

Table 6. Expression of Human SLC Transporter mRNAs in Various Tissues

Tissue SLC1A1 SLC1A2 SLC1A3 SLC1A4 SLC1A5 SLC2A1 SLC2A2 SLC2A3WSLC2A14 SLC2A4 Adrenal gland 0.00484 0.00406 0.00837 0.0921 0.0422 0.0194 BLQ 0.0842 0.00923 Bone marrow 0.00136 0.0000400 0.00803 0.0350 0.227 0.446 BLQ 0.868 0.00923 Brain 0.0467 0.555 0.215 0.0679 0.00184 0.127 BLQ 0.174 0.00158 Colon 0.0305 0.000101 0.00193 0.0169 0.144 0.0394 BLQ 0.0121 0.0125 Heart 0.0144 0.00514 0.0723 0.0149 0.0277 0.0851 BLQ 0.0845 0.241 Kidney 0.167 0.000141 0.000404 0.00532 0.137 0.0502 0.184 0.0334 0.00367 Liver 0.0367 0.0198 0.000676 0.0118 0.0112 0.00271 1.61 0.00996 0.00449 Lung 0.0672 0.000850 0.00204 0.00803 0.104 0.0201 BLQ 1.14 0.00167 Pancreas 0.00600 0.0112 0.00141 0.0848 0.0759 0.00945 BLQ 0.0183 0.000302 Peripheral leukocytes 0.00119 0.0000134 0.0000909 0.00692 0.0347 0.0361 BLQ 0.973 BLQ Placenta 0.0105 0.00353 0.00182 0.0157 0.221 7.36 BLQ 0.126 0.00156 Prostate 0.0367 0.000504 0.000918 0.0234 0.350 0.101 BLQ 0.0890 0.0106 Salivary gland 0.0112 0.00800 0.000635 0.0107 0.378 0.0314 BLQ 0.0148 0.0190 Skeletal muscle 0.0173 0.000514 0.0172 0.310 0.0472 0.0147 BLQ 0.0875 1.05 Small intestine 0.0912 0.0000673 0.000451 0.0181 0.0881 0.00962 0.159 0.0126 0.00879 Spinal cord 0.0247 0.396 0.145 0.0575 0.0344 0.200 BLQ 0.130 0.00282 Spleen 0.00108 0.000614 0.00407 0.0167 0.0833 0.0367 BLQ 0.169 0.0000347 Stomach 0.0135 0.00327 0.00132 0.0219 0.109 0.0218 BLQ 0.0391 0.0136 Testis 0.0123 0.00196 0.00177 0.0805 0.326 0.0401 BLQ 0.530 0.0118 Thymus 0.00161 0.000283 0.00130 0.0270 0.0548 0.0280 BLQ 0.0621 0.00237 Thyroid gland 0.103 0.00113 0.000977 0.00817 0.0261 0.0321 BLQ 0.0961 0.00558 Trachea 0.0294 0.00721 0.00172 0.0531 0.426 0.230 BLQ 0.171 0.00539 Uterus 0.0175 0.00227 0.000366 0.0324 0.0890 0.0511 BLQ 0.110 0.0157

ubiquitously and was expressed at the highest levels in tously. Kekuda et al.70) reported that SLC1A5 mRNA skeletal muscle, as was the case for ABCF1. was detectable in the human placenta, lung, skeletal Consistent with the ˆndings of other studies in human muscle, kidney, and pancreas. subjects,23,60) ABCG1 mRNA was expressed ubiquitous- SLC2A1 mRNA was expressed ubiquitously and was ly and was expressed at the highest levels in the adrenal expressed at the highest levels in the placenta, with gland. Similar to the ˆndings of other studies in human relatively high expression in the bone marrow, brain, subjects,61,62) ABCG2 mRNA was also expressed ubiqui- prostate, spinal cord, and trachea. Bell et al.71) reported tously and was expressed at high levels in the placenta, that SLC2A1 mRNA and protein are present at high small intestine, and uterus. Similar to the ˆndings of levels in the brain, with weak expression in the liver and another study in human subjects,60) ABCG4 mRNA was muscle. Consistent with the ˆndings of another study in expressed at high levels in the brain, spinal cord, and human subjects,72) SLC2A2 mRNA was most abundant testis. Consistent with the ˆndings of another study in in the liver and was detectable in the kidney and small the mouse,63) ABCG5 mRNA and ABCG8 mRNA were intestine. SLC2A3WSLC2A14 mRNA was expressed expressed at high levels in the liver and small intestine, ubiquitously. Similar to the ˆndings of other studies in with no or very weak expression in other tissues. human subjects73) and the mouse,74) SLC2A4 mRNA The mRNA expression levels of 108 human SLC was abundant in the heart and skeletal muscle. Similar transporters in various tissues are shown in Table 6. to the ˆndings of another study in human subjects,75) Similar to the ˆndings of another study in the mouse,64) SLC2A5 mRNA was expressed at high levels in the bone SLC1A1 mRNA was expressed ubiquitously. Consistent marrow, kidney, skeletal muscle, small intestine, and with the ˆndings of another study in human subjects,65) testis. Similar to the ˆndings of another study in human SLC1A2 mRNA was expressed at high levels in the subjects,76) SLC2A7 mRNA was expressed at high levels brain and spinal cord. Consistent with the ˆndings of in the small intestine and testis, with no or very weak other studies in human subjects,66,67) SLC1A3 mRNA expression in other tissues. Similar to the ˆndings of wasalsoexpressedathighlevelsinthebrainandspinal another study in the rat,77) SLC2A8 mRNA was cord. Consistent with the ˆndings of other studies in expressed ubiquitously and was expressed at the highest human subjects,68,69) SLC1A4 mRNA was expressed levels in the testis. Similar to the ˆndings of another ubiquitously and was expressed at the highest levels in study in human subjects,78) SLC2A9 mRNA was skeletal muscle. SLC1A5 mRNA was expressed ubiqui- expressed ubiquitously, was most abundant in the 464 Masuhiro NISHIMURA and Shinsaku NAITO

Table 6. (continued)

Tissue SLC2A5 SLC2A7 SLC2A8 SLC2A9 SLC2A10 SLC2A11 SLC2A12 SLC2A13 SLC3A1 SLC3A2 Adrenal gland 0.0136 BLQ 0.116 0.0148 0.0338 0.0322 0.0116 0.143 BLQ 0.372 Bone marrow 0.343 BLQ 0.0120 0.00650 0.0118 0.0122 0.00247 0.0450 BLQ 0.222 Brain 0.0201 BLQ 0.0434 0.00224 0.00687 0.0636 0.0723 0.415 0.000448 0.156 Colon 0.0214 BLQ 0.0352 0.00547 0.0454 0.0156 0.0106 0.123 0.00500 0.126 Heart 0.0284 BLQ 0.0447 0.0193 0.0254 0.0708 0.463 0.109 BLQ 0.106 Kidney 0.323 BLQ 0.0506 0.268 0.0104 0.199 0.0675 0.110 0.491 1.09 Liver 0.000428 BLQ 0.0581 0.0764 0.146 0.0123 0.0355 0.0335 0.0223 0.121 Lung 0.00189 BLQ 0.0255 0.0120 0.0451 0.0148 0.0759 0.0738 0.0000219 0.236 Pancreas 0.000960 BLQ 0.0195 0.00246 0.107 0.0470 0.00450 0.0604 0.0629 0.180 Peripheral leukocytes 0.00524 BLQ 0.00907 0.0184 0.0000998 0.0116 0.000683 0.0461 BLQ 0.225 Placenta 0.0303 BLQ 0.148 0.0278 0.0487 0.678 0.0203 0.0347 BLQ 1.91 Prostate 0.186 BLQ 0.0467 0.0175 0.189 0.0492 0.547 0.0397 0.000585 0.271 Salivary gland 0.00609 BLQ 0.0261 0.0915 0.0899 0.0369 0.0497 0.0715 BLQ 0.285 Skeletal muscle 0.993 BLQ 0.454 0.00731 0.0252 0.0863 0.254 0.0326 BLQ 0.697 Small intestine 0.618 0.0629 0.0513 0.0183 0.0210 0.0123 0.0285 0.0600 0.0207 0.225 Spinal cord 0.213 BLQ 0.0649 0.0103 0.0212 0.0550 0.0233 0.0494 0.0000515 0.357 Spleen 0.0229 BLQ 0.0439 0.00554 0.0116 0.0185 0.00110 0.0329 0.000155 0.180 Stomach 0.0105 0.0000814 0.0494 0.00514 0.0691 0.0210 0.0625 0.0591 0.000764 0.141 Testis 1.05 0.0235 0.532 0.00784 0.0360 0.0445 0.0168 0.178 0.00227 0.493 Thymus 0.0125 BLQ 0.00641 0.00704 0.00680 0.00907 0.00650 0.0213 BLQ 0.0980 Thyroid gland 0.00578 BLQ 0.0647 0.0280 0.112 0.0583 0.00752 0.0333 BLQ 0.239 Trachea 0.00861 BLQ 0.0359 0.0497 0.122 0.0239 0.0589 0.106 BLQ 0.291 Uterus 0.0134 BLQ 0.0577 0.00716 0.0585 0.0307 0.0918 0.125 0.00127 0.284

Table 6. (continued)

Tissue SLC4A1 SLC4A2 SLC4A3 SLC4A4 SLC4A7 SLC4A8 SLC4A9 SLC4A10 SLC4A11

Adrenal gland BLQ 0.00321 0.0114 0.00380 0.0226 0.0561 0.00103 0.000695 0.00643 Bone marrow 7.09 0.00177 0.000326 0.00387 0.0267 0.00702 0.000467 0.000555 0.000106 Brain BLQ 0.000577 0.0292 0.154 0.114 0.259 0.00208 0.0822 0.00198 Colon BLQ 0.00163 0.000790 0.243 0.0462 0.00481 0.000667 0.00885 0.000310 Heart BLQ 0.00132 0.333 0.0736 0.0477 0.00267 0.000516 0.000192 0.000676 Kidney 0.271 0.00461 0.00254 1.00 0.0445 0.0290 0.0682 0.0000741 0.0137 Liver 0.00152 0.00212 0.0000548 0.0652 0.00501 0.00112 0.000188 0.000287 0.000133 Lung BLQ 0.00273 0.000970 0.0591 0.0623 0.0168 0.000821 0.000375 0.00121 Pancreas BLQ 0.00232 0.00178 1.00 0.00846 0.00613 0.000478 0.000618 0.000219 Peripheral leukocytes 0.0154 0.00141 0.000452 0.00682 0.0830 0.0161 0.000240 0.00354 0.0000283 Placenta 0.131 0.0249 0.00423 0.00992 0.0135 0.00385 0.000504 0.0000472 0.000722 Prostate BLQ 0.00258 0.00692 0.412 0.0663 0.00476 0.00106 0.000577 0.00346 Salivary gland BLQ 0.00269 0.00277 0.00685 0.0298 0.0103 0.000307 0.0000376 0.0336 Skeletal muscle BLQ 0.00396 0.00124 0.0575 0.129 0.00108 0.000612 0.0000948 0.00353 Small intestine BLQ 0.00239 0.000930 0.0632 0.0595 0.00697 0.000656 0.000224 0.000225 Spinal cord 0.00897 0.00285 0.0238 0.329 0.0434 0.137 0.00306 0.00959 0.00170 Spleen 0.0264 0.00156 0.00396 0.00779 0.0537 0.0144 0.000205 0.00185 0.000196 Stomach BLQ 0.00354 0.00252 0.0623 0.0462 0.0149 0.000454 0.000416 0.00260 Testis BLQ 0.00258 0.0230 0.00716 0.150 0.564 0.0110 0.00178 0.0134 Thymus 0.00234 0.00106 0.00250 0.0101 0.0246 0.00687 0.000622 0.0000388 0.000740 Thyroid gland BLQ 0.00214 0.00233 0.218 0.0308 0.00306 0.00123 0.0000757 0.0162 Trachea BLQ 0.00202 0.00479 0.0402 0.0764 0.0522 0.000924 0.000262 0.0283 Uterus BLQ 0.00367 0.0161 0.00317 0.0368 0.00294 0.000589 0.0000925 0.00117

Table 6. (continued)

Tissue SLC5A1 SLC5A2 SLC5A3 SLC5A4 SLC5A5 SLC5A6 SLC5A7 SLC5A8 SLC5A10 SLC5A11 SLC5A12

Adrenal gland BLQ BLQ 0.191 0.00122 BLQ 0.0241 0.000740 0.0156 0.000439 0.000229 BLQ Bone marrow BLQ BLQ 0.108 0.00154 0.00131 0.0117 BLQ BLQ 0.00468 0.000220 BLQ Brain 0.000918 BLQ 0.117 0.000686 0.00444 0.0172 0.000126 0.00302 0.0000721 0.0540 0.000166 Colon 0.0436 BLQ 0.119 0.000583 BLQ 0.0211 0.00120 0.00153 0.000138 0.000331 BLQ Heart 0.622 BLQ 0.139 0.00111 BLQ 0.0158 0.00100 BLQ 0.000111 0.000343 0.00402 Kidney 0.0665 0.212 0.527 0.00175 BLQ 0.0238 0.000199 0.148 0.342 0.0890 1.71 Liver 0.00498 BLQ 0.0625 0.000460 BLQ 0.0437 0.0000160 BLQ 0.000230 0.00438 0.00100 Lung 0.00650 BLQ 0.222 0.00664 0.00110 0.0130 0.000154 0.00354 0.000437 0.000665 BLQ Pancreas 0.00281 BLQ 0.0427 0.000261 BLQ 0.0147 0.0000863 BLQ 0.0000323 0.000142 BLQ Peripheral leukocytes BLQ BLQ 0.128 BLQ 0.00282 0.00873 BLQ BLQ 0.00124 0.000408 BLQ Placenta 0.0000438 BLQ 0.131 0.000113 BLQ 1.03 BLQ BLQ 0.000431 0.000810 BLQ Prostate 0.0218 BLQ 0.145 0.00212 0.000310 0.0180 0.000589 0.0537 0.000118 0.000308 BLQ Salivary gland 0.0243 BLQ 0.0623 0.000665 0.850 0.0244 0.000258 0.0320 0.0000819 0.000179 BLQ Skeletal muscle 0.00489 BLQ 0.153 0.000567 BLQ 0.0696 0.000145 BLQ 0.0000945 0.000475 BLQ Small intestine 1.83 BLQ 0.0819 0.0470 0.000997 0.0430 0.00103 BLQ 0.000161 0.0248 0.124 Spinal cord 0.00126 BLQ 0.128 0.00209 0.0155 0.0273 0.0232 0.00279 0.000116 0.226 0.000346 Spleen BLQ BLQ 0.0836 0.000930 0.00157 0.0176 0.0000348 BLQ 0.00178 0.000672 BLQ Stomach 0.0431 BLQ 0.138 0.00112 0.176 0.0201 0.00103 BLQ 0.000172 0.0000778 BLQ Testis 0.0276 BLQ 0.570 0.00297 0.00576 0.217 0.000285 0.0106 0.00109 0.00294 0.00128 Thymus 0.000252 BLQ 0.0977 0.000237 0.000338 0.0141 0.0000059 0.00237 0.00144 0.000225 BLQ Thyroid gland 0.00172 BLQ 1.63 0.00479 1.22 0.0166 0.00142 0.299 0.000123 0.000171 BLQ Trachea 0.291 BLQ 0.222 0.00156 0.00391 0.0132 0.000785 0.249 0.000150 0.000265 BLQ Uterus 0.00457 BLQ 0.136 0.00716 0.000633 0.0216 0.000518 0.00858 0.000312 0.000296 0.00457

Table 6. (continued)

Tissue SLC6A2 SLC6A3 SLC6A4 SLC6A5 SLC6A6 SLC6A7 SLC6A9

Adrenal gland 0.0243 0.0000928 0.000527 0.000238 0.357 BLQ 0.0991 Bone marrow BLQ BLQ 0.00271 BLQ 0.171 BLQ 0.0501 Brain 0.0000273 BLQ 0.000557 0.00545 0.0480 0.0257 0.0209 Colon 0.0000797 BLQ 0.00297 BLQ 0.0298 0.00584 0.0165 Heart 0.0000869 BLQ 0.00286 0.000272 0.116 0.0000456 0.00332 Kidney 0.000308 0.00133 0.00186 BLQ 0.110 0.0000048 0.00457 Liver 0.000283 BLQ 0.0000256 BLQ 0.00659 BLQ 0.000250 Lung 0.000176 0.00327 1.21 BLQ 0.0866 BLQ 0.0144 Pancreas BLQ BLQ 0.00468 0.0000964 0.00626 BLQ 0.00576 Peripheral leukocytes BLQ BLQ 0.00345 BLQ 0.249 BLQ 0.0000643 Placenta 0.331 BLQ 0.226 0.0000201 0.333 0.0000085 0.0103 Prostate 0.00104 0.000990 0.000997 0.0000282 0.0480 0.0000047 0.00635 Salivary gland 0.00232 BLQ 0.0000373 0.0000479 0.0696 0.0000068 0.0132 Skeletal muscle 0.000914 BLQ 0.000488 0.0000744 0.233 BLQ 0.000688 Small intestine 0.000165 0.00109 0.117 0.0000128 0.128 0.00182 0.00870 Spinal cord 0.000235 0.000133 0.000847 0.0632 0.0575 0.00125 0.120 Spleen BLQ BLQ 0.00215 0.0000220 0.243 BLQ 0.00175 Stomach 0.000431 BLQ 0.00131 0.0000167 0.0725 0.0000106 0.00932 Testis 0.0450 0.00427 0.00476 0.0115 0.0600 0.0000382 0.00283 Thymus 0.0000579 0.00484 0.000134 0.0000773 0.0548 0.0000106 0.00191 Thyroid gland 0.000185 0.00267 0.00145 0.0000221 0.0715 BLQ 0.00541 Trachea 0.000874 0.000118 0.00129 0.0000255 0.434 BLQ 0.0243 Uterus 0.00285 0.000480 0.000298 BLQ 0.143 0.0000034 0.0199

BLQ, below the limit of quantiˆcation. Data are expressed as the ratio of the target mRNA to PPIA mRNA. Experiments were performed in duplicate. The highest values among the various tissues are shown in boxes. kidney, and was expressed at relatively high levels in the subjects,81) SLC3A1 mRNA was expressed at high levels liver and salivary gland. Similar to the ˆndings of other in the kidney, liver, pancreas, and small intestine, with studies,74,79,80) SLC2A10 mRNA, SLC2A11 mRNA, no or very weak expression in other tissues. Similar to SLC2A12 mRNA, and SLC2A13 mRNA were also the ˆndings of another study in the mouse,82) SLC3A2 expressed ubiquitously. mRNA was expressed ubiquitously. Similar to the ˆndings of another study in human SLC4A1 mRNA was most abundant in the bone 466 Masuhiro NISHIMURA and Shinsaku NAITO

Table 6. (continued)

Tissue SLC7A1 SLC7A2 SLC7A3 SLC7A4 SLC7A5 SLC7A6 SLC7A7 SLC7A8 SLC7A9 SLC7A10 SLC7A11 SLC7A13

Adrenal gland 0.0165 0.0573 0.0000564 0.0114 0.0163 0.0221 0.0354 0.0319 0.00141 0.0123 0.000850 BLQ Bone marrow 0.0360 0.0147 0.0000407 0.0000814 0.0974 0.0102 0.0944 0.0106 0.000616 0.0241 0.00897 BLQ Brain 0.0302 0.0304 0.00198 0.0227 0.0188 0.0145 0.0104 0.0197 0.00272 0.0415 0.125 0.0000444 Colon 0.0238 0.0121 0.000214 0.00932 0.0378 0.0103 0.0310 0.0180 0.000844 0.0152 0.00800 BLQ Heart 0.0140 0.0869 0.0000881 0.00303 0.00779 0.0472 0.0179 0.0154 0.000649 0.00554 0.00493 0.0000239 Kidney 0.00737 0.0308 0.0000837 0.00115 0.00535 0.0109 1.53 0.779 0.874 0.00671 0.000341 0.246 Liver 0.00120 0.467 0.0000421 0.000953 0.00187 0.000782 0.0359 0.00809 0.0778 BLQ 0.000534 BLQ Lung 0.00962 0.0836 0.000146 0.00444 0.0537 0.0237 0.124 0.0201 0.00145 0.000282 0.0101 BLQ Pancreas 0.0788 0.271 0.0000875 0.000459 0.00425 0.00483 0.0196 0.0344 0.00103 0.000616 0.00852 BLQ Peripheral leukocytes 0.00787 BLQ 0.0000677 0.0000654 0.0833 0.0508 0.503 0.00190 0.000790 0.000322 0.00101 BLQ Placenta 0.124 1.56 0.0000781 0.578 0.0890 0.0334 0.104 0.473 0.00134 0.0387 0.00271 BLQ Prostate 0.0349 0.152 0.00447 0.0242 0.0208 0.00999 0.0162 0.168 0.00582 0.000416 0.0152 0.000111 Salivary gland 0.0540 0.0181 0.000354 0.00682 0.0178 0.0117 0.0181 0.0495 0.000934 0.00694 0.000943 BLQ Skeletal muscle 0.00932 2.27 0.000115 0.000836 0.0301 0.129 0.0448 0.0741 0.00264 0.0136 0.000902 0.0000878 Small intestine 0.0250 0.0154 0.000332 0.00564 0.0443 0.00939 0.260 0.0585 0.249 0.0105 0.00749 BLQ Spinal cord 0.0513 0.154 0.000947 0.00832 0.0775 0.00817 0.0418 0.0198 0.00317 0.0405 0.245 0.0000380 Spleen 0.0118 0.0173 0.0000442 0.00259 0.0205 0.0342 0.261 0.0454 0.00137 0.000727 0.00219 BLQ Stomach 0.0196 0.0236 0.00149 0.00910 0.00919 0.0129 0.0526 0.0912 0.00549 0.000841 0.0243 BLQ Testis 0.0718 0.362 0.00965 0.460 0.171 0.0682 0.282 0.166 0.0115 0.0156 0.0263 0.000229 Thymus 0.0106 0.0102 0.0414 0.00146 0.0216 0.105 0.0249 0.00617 0.00108 0.00702 0.00314 BLQ Thyroid gland 0.0158 0.198 0.000231 0.00101 0.0178 0.0227 0.0268 0.0736 0.00414 0.00491 0.0215 BLQ Trachea 0.0393 0.128 0.000167 0.0130 0.0696 0.0198 0.0422 0.0627 0.00275 0.00776 0.0337 BLQ Uterus 0.0215 0.0964 0.0141 0.00419 0.0244 0.0119 0.0363 0.0693 0.00541 0.000233 0.00177 0.0000447

Table 6. (continued)

Tissue SLC10A1 SLC10A2 SLC10A3 SLC10A4 SLC10A5 SLC15A1 SLC15A2 SLC15A3 SLC15A4

Adrenal gland 0.00152 0.0000067 0.0805 0.0123 0.000301 BLQ 0.00287 0.0407 0.0751 Bone marrow 0.000802 BLQ 0.0786 0.00352 0.000248 BLQ 0.0214 0.0706 0.224 Brain 0.00260 0.0000094 0.0176 0.00891 0.00203 BLQ 0.0271 0.00952 0.0663 Colon 0.00174 0.000241 0.0495 0.00224 0.00635 0.0110 0.00127 0.0361 0.0447 Heart 0.00118 0.0000133 0.0756 0.00141 0.00121 BLQ 0.0148 0.0467 0.0957 Kidney 0.00185 0.0565 0.0533 0.000276 0.0106 0.0292 0.0297 0.0143 0.0778 Liver 0.486 BLQ 0.0140 0.0000974 0.0172 0.0522 0.000631 0.0276 0.0689 Lung 0.00244 BLQ 0.0736 0.00141 0.000686 BLQ 0.0456 0.135 0.105 Pancreas 0.000439 0.0000632 0.0408 0.000442 0.000756 0.0155 0.00438 0.00763 0.0504 Peripheral leukocytes 0.0194 BLQ 0.0736 0.000547 0.000401 BLQ 0.00549 0.163 0.333 Placenta 0.00246 BLQ 0.370 0.00174 0.0000894 0.00635 0.00131 0.283 0.112 Prostate 0.000499 0.0000220 0.0696 0.00154 0.00326 0.00673 0.202 0.0249 0.0931 Salivary gland 0.000774 BLQ 0.0365 0.0261 0.000573 BLQ 0.0474 0.0166 0.0780 Skeletal muscle 0.00535 0.00122 0.131 0.00537 0.00134 BLQ 0.00205 0.0506 0.607 Small intestine 0.00138 0.0902 0.0408 0.00259 0.0111 0.148 0.000804 0.0509 0.0533 Spinal cord 0.000816 0.0000168 0.0292 0.0379 0.000633 BLQ 0.0246 0.0780 0.115 Spleen 0.00113 0.0000389 0.0610 0.000391 0.000322 BLQ 0.0111 0.222 0.164 Stomach 0.000725 0.000302 0.0629 0.00125 0.00481 0.00264 0.00776 0.0368 0.0778 Testis 0.00570 0.0000919 0.0951 0.00699 0.000883 0.000649 0.0235 0.0365 0.378 Thymus 0.00164 0.0000058 0.0344 0.000320 0.000341 0.000339 0.00243 0.0397 0.123 Thyroid gland 0.000911 0.0000235 0.0741 0.00247 0.00108 0.00113 0.0212 0.0172 0.0718 Trachea 0.00292 BLQ 0.0701 0.000595 0.00530 0.00101 0.0830 0.0337 0.0981 Uterus 0.000446 0.0000231 0.0951 0.000868 0.000379 0.0113 0.00388 0.0554 0.144

BLQ, below the limit of quantiˆcation. Data are expressed as the ratio of the target mRNA to PPIA mRNA. Experiments were performed in duplicate. The highest values among the various tissues are shown in boxes. marrow and was detectable in the kidney, liver, abundant in the kidney and pancreas. SLC4A7 mRNA peripheral leukocytes, placenta, spinal cord, spleen, and was expressed ubiquitously. Consistent with the ˆndings thymus. SLC4A2 mRNA and SLC4A3 mRNA were of another study in human subjects,85) SLC4A8 mRNA expressed ubiquitously and were expressed at the highest was expressed ubiquitously and was expressed at higher levels in the placenta and heart, respectively. Similar to levels in the brain, spinal cord, and testis. Consistent the ˆndings of other studies in human subjects,83,84) with the ˆndings of another study in human subjects,86) SLC4A4 mRNA was expressed ubiquitously and was SLC4A9 mRNA was abundant in the kidney, with weak mRNA Expression Proˆles of Human Drug Transporters 467

Table 6. (continued)

Tissue SLC21A3 SLC21A6 SLC21A9 SLC21A11 SLC21A12 SLC21A14 SLC21A15 Adrenal gland 0.0000132 0.000263 0.0319 0.0201 0.00916 0.000105 0.000132 Bone marrow 0.0000131 BLQ 0.00632 0.0431 0.0102 0.00116 0.00637 Brain 0.0825 0.0000357 0.00975 0.0283 0.0200 0.0409 0.00178 Colon 0.0000107 BLQ 0.0120 0.0167 0.0139 0.000219 0.00176 Heart 0.000442 0.000208 0.00975 0.0725 0.00996 0.00273 0.0311 Kidney 0.00199 BLQ 0.0262 0.0160 0.0169 0.000135 0.000319 Liver 0.00324 0.252 0.0677 0.00549 0.00100 BLQ 0.0000718 Lung 0.00429 0.0000101 0.0314 0.0608 0.0741 0.00248 0.00115 Pancreas 0.000114 BLQ 0.00471 0.00419 0.00414 0.000114 0.000877 Peripheral leukocytes 0.0000219 BLQ BLQ 0.0842 0.000810 BLQ 0.000468 Placenta 0.000130 BLQ 0.0557 0.00580 0.0501 BLQ 0.000656 Prostate 0.00151 0.0000773 0.00423 0.0202 0.00979 0.000224 0.0178 Salivary gland 0.00316 BLQ 0.00494 0.00630 0.00671 BLQ 0.00133 Skeletal muscle 0.0000596 0.000163 0.00907 0.0425 0.0161 BLQ 0.481 Small intestine 0.0000198 BLQ 0.0277 0.0106 0.00711 0.000303 0.00185 Spinal cord 0.148 0.0000845 0.0318 0.104 0.0131 0.0317 0.00145 Spleen 0.00148 BLQ 0.0233 0.0331 0.00289 BLQ 0.00214 Stomach 0.000138 BLQ 0.00646 0.0114 0.0150 0.0000670 0.00350 Testis 0.00403 0.00357 0.00929 0.284 0.0110 0.00639 0.00702 Thymus 0.0000912 BLQ 0.00870 0.00600 0.00639 0.000270 0.0184 Thyroid gland 0.000428 0.0000339 0.00564 0.0354 0.00348 0.000862 0.00100 Trachea 0.0131 0.000150 0.00692 0.0167 0.0158 0.00189 0.00247 Uterus 0.0000267 0.0000831 0.0111 0.0158 0.0112 BLQ 0.00127

Table 6. (continued)

Tissue SLC22A1 SLC22A2 SLC22A3 SLC22A4 SLC22A5 SLC22A6 SLC22A7 SLC22A8 SLC22A9

Adrenal gland 0.00151 BLQ 0.133 0.00301 0.00864 0.0000072 0.000330 BLQ 0.0000157 Bone marrow 0.000137 BLQ 0.0203 0.0249 0.00254 BLQ 0.0000848 BLQ BLQ Brain 0.0000706 0.0000494 0.00578 0.00217 0.00435 0.00114 0.000555 0.000504 0.00119 Colon 0.0000285 0.0000208 0.0327 0.00244 0.0116 BLQ 0.0000160 BLQ 0.0000199 Heart 0.000182 BLQ 0.0297 0.00209 0.0125 0.0000228 0.00136 BLQ 0.0000201 Kidney 0.00389 0.139 0.0499 0.0274 0.0511 0.853 0.471 0.818 0.000206 Liver 2.23 0.0000367 0.124 0.000202 0.00248 0.0000606 0.818 0.000135 0.0343 Lung 0.0000684 BLQ 0.0501 0.00904 0.00425 0.0000067 0.0000264 BLQ 0.000101 Pancreas 0.0000413 BLQ 0.00367 0.000177 0.00422 BLQ 0.0000945 BLQ 0.0000154 Peripheral leukocytes 0.000237 BLQ BLQ 0.00246 0.00143 BLQ 0.000160 BLQ 0.0000078 Placenta 0.0000830 0.0000884 0.146 0.00582 0.0338 BLQ 0.0000503 BLQ BLQ Prostate 0.000464 BLQ 0.376 0.00923 0.0171 BLQ 0.000232 BLQ 0.0000134 Salivary gland 0.000309 BLQ 0.486 0.000398 0.00707 0.0000305 0.0000249 BLQ BLQ Skeletal muscle 0.00105 BLQ 0.895 0.00747 0.0612 BLQ 0.000201 BLQ BLQ Small intestine 0.0000241 BLQ 0.0256 0.00694 0.0136 BLQ 0.000686 BLQ BLQ Spinal cord 0.0000477 0.00117 0.0243 0.0136 0.00664 0.00594 0.000205 0.00136 0.0000116 Spleen 0.000178 BLQ 0.00317 0.00149 0.00213 BLQ 0.000170 BLQ 0.0000435 Stomach 0.000130 0.0000204 0.0330 0.000575 0.00466 BLQ 0.0000129 BLQ 0.000165 Testis 0.00128 0.000242 0.0470 0.00114 0.0105 0.0000192 0.0193 BLQ 0.000191 Thymus 0.0000539 0.0000062 0.00699 0.000415 0.00238 0.0000040 0.0000759 BLQ BLQ Thyroid gland 0.000331 BLQ 0.0230 0.000465 0.00734 0.0000173 0.0000617 BLQ 0.0000066 Trachea 0.000161 0.000116 0.105 0.0246 0.00668 0.0000146 0.0000632 0.0000414 0.0000423 Uterus 0.000327 0.0000221 0.135 0.00112 0.00551 0.0000442 0.000116 0.0000404 0.0000184

Table 6. (continued)

Tissue SLC22A11 SLC22A12 SLC22A13 SLC22A14 SLC22A15 SLC22A16 SLC22A17 SLC22A18 Adrenal gland BLQ BLQ 0.000239 0.000114 0.0173 0.000103 0.157 0.00795 Bone marrow BLQ BLQ 0.0000985 0.000676 0.153 0.151 0.0192 0.0112 Brain BLQ BLQ 0.00113 0.00119 0.0518 0.0000306 1.36 0.00652 Colon BLQ BLQ 0.000182 0.0000794 0.00384 0.0000204 0.0606 0.115 Heart BLQ BLQ 0.000103 0.000177 0.0313 0.000112 0.101 0.0625 Kidney 0.125 0.976 0.0548 0.00235 0.0110 0.0000389 0.121 0.238 Liver BLQ BLQ 0.000112 0.0000765 0.00160 0.000114 0.0107 0.0830 Lung BLQ BLQ 0.000133 0.0000775 0.0153 0.000246 0.0531 0.00952 Pancreas BLQ BLQ 0.000106 0.0000295 0.00609 0.0000663 0.0477 0.00449 Peripheral leukocytes BLQ BLQ 0.000425 0.000118 0.0238 0.00162 0.00737 0.0181 Placenta 0.106 BLQ 0.000544 0.000139 0.00734 0.000320 0.0550 0.0275 Prostate BLQ BLQ 0.000292 0.000205 0.00885 0.000186 0.380 0.0311 Salivary gland BLQ BLQ 0.000128 0.000110 0.0109 0.000123 0.255 0.0480 Skeletal muscle BLQ BLQ 0.00146 0.00243 0.00436 0.000462 0.0431 0.00429 Small intestine BLQ BLQ 0.000329 0.0000573 0.00242 0.0000207 0.0974 0.129 Spinal cord BLQ BLQ 0.000237 0.000665 0.0634 0.000159 0.979 0.00913 Spleen BLQ BLQ 0.000106 0.0000773 0.00817 0.000374 0.0291 0.0185 Stomach BLQ BLQ 0.000176 0.0000390 0.00737 0.0000566 0.0616 0.0343 Testis BLQ 0.000175 0.000908 0.0893 0.0152 0.0902 0.203 0.0600 Thymus BLQ BLQ 0.000118 0.0000906 0.00136 0.00157 0.0162 0.00639 Thyroid gland BLQ BLQ 0.000136 0.0000900 0.00923 0.0000659 0.175 0.0377 Trachea BLQ BLQ 0.000373 0.0000684 0.00952 0.00310 0.205 0.0447 Uterus BLQ BLQ 0.000257 0.000154 0.00402 0.00367 0.138 0.0147

Table 6. (continued)

Tissue SLC28A1 SLC28A2 SLC28A3 SLC29A1 SLC29A2 SLC29A3 SLC29A4

Adrenal gland 0.000120 0.0000857 0.0000161 0.122 0.000681 0.00180 0.00160 Bone marrow 0.0000168 BLQ 0.0243 0.0526 0.000799 0.00168 0.0000981 Brain 0.0000866 0.0000174 0.0000324 0.0156 0.00726 0.00184 0.00236 Colon 0.0000234 0.000587 0.00212 0.0383 0.00926 0.00151 0.000547 Heart 0.000583 BLQ 0.000987 0.225 0.0113 0.00123 0.000836 Kidney 0.0778 0.00335 0.0000663 0.0213 0.00724 0.00197 0.000676 Liver 0.0348 0.000213 0.000374 0.0614 0.000394 0.00226 0.0000530 Lung 0.0000243 0.0000342 0.00193 0.0268 0.00284 0.00215 0.000186 Pancreas 0.0000180 BLQ 0.0200 0.0267 0.00372 0.00137 0.00133 Peripheral leukocytes 0.0000080 BLQ 0.000522 0.00560 0.00148 0.00179 0.0000135 Placenta 0.0103 0.000500 0.000493 0.0656 0.00455 0.0236 0.000107 Prostate 0.0000550 0.0000087 0.00186 0.0178 0.00724 0.00259 0.00313 Salivary gland 0.000211 BLQ 0.00172 0.0443 0.00643 0.00326 0.000662 Skeletal muscle 0.000483 BLQ BLQ 0.454 0.300 0.00108 0.00246 Small intestine 0.0109 0.0616 0.00332 0.0302 0.00602 0.00221 0.00249 Spinal cord 0.00209 0.000205 0.000329 0.0147 0.00702 0.00366 0.00507 Spleen 0.0000169 BLQ 0.000318 0.0115 0.00163 0.00439 0.000187 Stomach 0.0000408 0.0153 0.00789 0.0561 0.00558 0.00281 0.000490 Testis 0.000348 0.000470 0.00246 0.0433 0.00102 0.00537 0.00177 Thymus 0.0000181 BLQ 0.000892 0.0608 0.00283 0.00213 0.000324 Thyroid gland 0.0000517 0.0000733 0.000320 0.0542 0.00605 0.00263 0.00419 Trachea 0.000117 0.000147 0.0218 0.0334 0.00483 0.00252 0.000740 Uterus 0.000338 0.000712 0.00119 0.0492 0.00134 0.00484 0.00182

Table 6. (continued)

Tissue SLC36A1 SLC36A2 SLC36A3 SLC36A4 SLC38A1 SLC38A2 SLC38A3 SLC38A4 SLC38A5 SLC38A6 Adrenal gland 0.0169 BLQ BLQ 0.0246 0.0149 0.185 0.000462 0.00144 0.00164 0.00792 Bone marrow 0.105 BLQ BLQ 0.140 0.0640 0.0822 0.000587 0.00267 0.0619 0.00271 Brain 0.0649 BLQ BLQ 0.0459 0.147 0.0845 0.0190 0.000419 0.0137 0.00888 Colon 0.0377 BLQ BLQ 0.0190 0.139 0.0461 0.000207 0.00489 0.0129 0.00299 Heart 0.00729 BLQ BLQ 0.0401 0.541 0.151 0.0128 0.00261 0.00302 0.00465 Kidney 0.0220 0.871 BLQ 0.0212 0.0368 0.0571 0.0344 0.00714 0.00137 0.0121 Liver 0.00486 BLQ BLQ 0.00666 0.0138 0.0554 0.880 0.195 0.000345 0.00376 Lung 0.00755 BLQ BLQ 0.0226 0.0542 0.232 0.000353 0.00145 0.0186 0.00574 Pancreas 0.00680 BLQ BLQ 0.0105 0.109 0.0487 0.0499 0.0122 0.275 0.00235 Peripheral leukocytes 0.0155 BLQ BLQ 0.0517 0.193 0.0499 BLQ 0.00112 0.00781 0.00262 Placenta 0.0169 BLQ BLQ 0.0238 0.660 0.367 0.00295 0.00109 0.00549 0.00491 Prostate 0.0723 BLQ BLQ 0.0286 0.119 0.121 0.000987 0.00387 0.00455 0.00682 Salivary gland 0.0141 BLQ BLQ 0.0188 0.0640 0.112 0.00276 0.000830 0.0387 0.00837 Skeletal muscle 0.0627 1.71 BLQ 0.0283 0.256 0.871 0.222 0.0538 0.00199 0.0141 Small intestine 0.0529 BLQ BLQ 0.00803 0.0743 0.0268 0.00187 0.00141 0.0180 0.00324 Spinal cord 0.0184 BLQ BLQ 0.0552 0.322 0.106 0.0733 0.000947 0.0267 0.00861 Spleen 0.0160 BLQ BLQ 0.0208 0.131 0.0595 0.000105 0.000908 0.00803 0.00729 Stomach 0.0158 BLQ BLQ 0.0241 0.0811 0.0748 0.00218 0.00244 0.0169 0.00435 Testis 0.0878 BLQ 0.0145 0.0398 0.0112 0.0878 0.0112 0.00156 0.00189 0.0196 Thymus 0.0327 BLQ BLQ 0.00888 0.0720 0.0569 0.000141 0.000561 0.00724 0.00280 Thyroid gland 0.00929 BLQ BLQ 0.0400 0.120 0.0748 0.00385 0.00381 0.0381 0.00913 Trachea 0.0160 BLQ BLQ 0.0185 0.0954 0.152 0.00457 0.00219 0.0179 0.0100 Uterus 0.00939 BLQ BLQ 0.0228 0.0479 0.124 0.000622 0.00185 0.0111 0.00503

BLQ, below the limit of quantiˆcation. Data are expressed as the ratio of the target mRNA to PPIA mRNA. Experiments were performed in duplicate. The highest values among the various tissues are shown in boxes. expression in other tissues. Consistent with the ˆndings or very weak expression in other tissues. SLC5A8 of another study in the rat,87) SLC4A10 mRNA was mRNA was expressed at high levels in the kidney, most abundant in the brain, with weak expression in thyroid gland, and trachea. Similar to the ˆndings of other tissues. Consistent with the ˆndings of another another study in the cow,90) SLC5A10 mRNA was study in human subjects,86) SLC4A11 mRNA was expressed at the highest levels in the kidney, with very expressed at high levels in the kidney, salivary gland, weak expression in other tissues. SLC5A11 mRNA was testis, thyroid gland, and trachea, with weak expression expressed at the highest levels in the spinal cord and was in other tissues. expressed at relatively high levels in the brain, kidney Similar to the ˆndings of other studies in the rabbit,88) and small intestine, with very weak expression in other the rat,89) and the cow,90) SLC5A1 mRNA was most tissues. SLC5A12 mRNA was expressed at the highest abundant in the small intestine and was expressed at levels in the kidney and was expressed at relatively high relatively high levels in the heart and trachea. Similar to levels in the small intestine, with no or very weak expres- the ˆndings of another study in the rat,91) SLC5A2 sion in other tissues. mRNA was abundant in the kidney, with no expression SLC6A2 mRNA was expressed at the highest levels in in other tissues. Similar to the ˆndings of another study the placenta and was expressed at relatively high levels in human subjects,92) SLC5A3 mRNA was expressed in the adrenal gland and testis, with no or very weak ubiquitously and was expressed at high levels in the expression in other tissues. SLC6A3 mRNA showed no kidney, testis, and thyroid gland. SLC5A4 mRNA was or very weak expression in all tissues. Consistent with expressed at the highest levels in the small intestine, with the ˆndings of another study in human subjects,95) no or very weak expression in other tissues. Similar to SLC6A4 mRNA was expressed ubiquitously, was the ˆndings of another study in human subjects,93) expressed at the highest levels in the lung, and was SLC5A5 mRNA was expressed at the highest levels in expressed at relatively high levels in the placenta and the thyroid gland and was expressed at relatively high small intestine. SLC6A5 mRNA was expressed at high levels in the salivary gland and stomach, with no or very levels in the spinal cord and testis, with no or very weak weak expression in other tissues. Consistent with the expression in other tissues. SLC6A6 mRNA was ˆndings of another study in human subjects,94) SLC5A6 expressed ubiquitously. Consistent with the ˆndings of mRNA was expressed ubiquitously and was expressed at another study in human subjects,96) SLC6A7 mRNA the highest levels in the placenta. SLC5A7 mRNA was was expressed at the highest levels in the brain, with no expressed at the highest levels in the spinal cord, with no or very weak expression in other tissues. SLC6A9 470 Masuhiro NISHIMURA and Shinsaku NAITO mRNA was expressed ubiquitously and was expressed at SLC15A3 mRNA was expressed at high levels in the the highest levels in the spinal cord. lung, peripheral leukocytes, placenta, and spleen. On SLC7A1 mRNA was expressed ubiquitously and was the other hand, SLC15A4 mRNA was expressed at the expressed at the highest levels in the placenta. Similar to highest levels in skeletal muscle. the ˆndings of another study in human subjects,97) SLC21A3 mRNA was expressed at high levels in the SLC7A2 mRNA was expressed ubiquitously except in brain, spinal cord, and trachea, with very weak expres- peripheral leukocytes and was expressed at high levels in sion in other tissues. SLC21A6 mRNA was expressed at the placenta and skeletal muscle. Similar to the ˆndings the highest levels in the liver, with no or very weak of another study in the rat,98) SLC7A3 mRNA was expression in other tissues. SLC21A9 mRNA was expressed at high levels in the brain, prostate, spinal expressed ubiquitously except in peripheral leukocytes cord, stomach, testis, thymus, and uterus. SLC7A4 and was expressed at the highest levels in the liver. mRNA was expressed ubiquitously and was expressed at SLC21A11 mRNA and SLC21A12 mRNA were high levels in the placenta and testis. SLC7A5 mRNA expressed ubiquitously and were expressed at the highest was expressed ubiquitously and was expressed at the levels in the testis and placenta, respectively. The results highest levels in the testis. SLC7A6 mRNA was also for SLC21A3, SLC21A6, SLC21A9, SLC21A11, and expressed ubiquitously and was expressed at the highest SLC21A12 were similar to those reported in human levels in skeletal muscle. Consistent with the ˆndings of subjects.109–112) Consistent with the ˆndings of another another study in human subjects,99) SLC7A7 mRNA study in human subjects,113) SLC21A14 mRNA was was expressed ubiquitously and was expressed at high expressed at high levels in the brain, spinal cord, and levels in the kidney and peripheral leukocytes. Both testis, with no or weak expression in other tissues. SLC7A8 mRNA and SLC7A9 mRNA were also SLC21A15 mRNA was expressed ubiquitously and was expressed ubiquitously and were expressed at the highest expressed at the highest levels in skeletal muscle. levels in the kidney. Similar to the ˆndings of other SLC22A1 mRNA was expressed at the highest levels studies in human subjects100) and the mouse,101) in the liver, with very weak expression in other tissues. SLC7A10 mRNA was expressed ubiquitously except in However, in the rat, SLC22A1 mRNA was expressed at the liver and was expressed at high levels in the brain, the highest levels in the kidney.114) Consistent with the placenta, and spinal cord. Similar to the ˆndings of ˆndings of another study in the rat,114) SLC22A2 mRNA another study in the mouse,102) SLC7A11 mRNA was was expressed at the highest levels in the kidney, with no expressed ubiquitously and was expressed at high levels or very weak expression in other tissues; SLC22A3 in the brain and spinal cord. Similar to the ˆndings of mRNA was expressed ubiquitously except in peripheral other studies in human subjects103) and the mouse,104) leukocytes and was expressed at the highest levels in SLC7A13 mRNA was most abundant in the kidney and skeletal muscle; SLC22A4 mRNA was expressed ubiqui- was only very weakly detectable in the brain, heart, tously and was expressed at the highest levels in the prostate, skeletal muscle, spinal cord, testis, and uterus. kidney; and SLC22A5 mRNA was expressed ubiqui- SLC10A1 mRNA was expressed ubiquitously and was tously and was expressed at high levels in the kidney and most abundant in the liver. Similar to the ˆndings of skeletal muscle. Consistent with the ˆndings of other another study in the mouse,48) SLC10A2 mRNA was studies in human subjects,115,116) SLC22A6 mRNA was expressed at high levels in the kidney and small intes- expressed at the highest levels in the kidney, with no or tine, with no or very weak expression in other tissues. very weak expression in other tissues. Consistent with SLC10A3 mRNA, SLC10A4 mRNA, and SLC10A5 the ˆndings of another study in human subjects,115) mRNA were expressed ubiquitously and were expressed SLC22A7 mRNA was expressed at high levels in the at the highest levels in the placenta, spinal cord, and kidney, liver, and testis, with very weak expression in liver, respectively. other tissues. Consistent with the ˆndings of other Similar to the ˆndings of other studies105,106) in the rat, studies in human subjects,115,117) SLC22A8 mRNA was sheep, dairy cow, pig, and chicken, SLC15A1 mRNA expressed at the highest levels in the kidney, with no or was most abundant in the small intestine and was detect- very weak expression in other tissues. Consistent with able in the colon, kidney, liver, pancreas, placenta, the ˆndings of another study in human subjects,115) prostate, stomach, testis, thymus, thyroid gland, SLC22A9 mRNA was expressed at the highest levels trachea, and uterus. SLC15A2 mRNA was expressed in the liver, with no or very weak expression in other ubiquitously and was expressed at the highest levels in tissues. SLC22A11 mRNA was expressed at high levels the prostate. Saito et al.107) reported that the mRNA in the kidney and placenta, with no expression in other expression of rat SLC15A2 mRNA was predominant in tissues. Consistent with the ˆndings of another study in the kidney. SLC15A3 mRNA and SLC15A4 mRNA human subjects,118) SLC22A12 mRNA was expressed at were expressed ubiquitously. Furthermore, consistent high levels in the kidney and was expressed at very low with the ˆndings of another study in human subjects,108) levels in the testis, with no expression in other tissues. mRNA Expression Proˆles of Human Drug Transporters 471

Similar to the ˆndings of another study in human sub- barrier). One example of the involvement of speciˆc jects,119) SLC22A13 mRNA and SLC22A14 mRNA were ABC and SLC transporters in drug delivery to the liver expressed ubiquitously and were expressed at the highest is described here. The most well-known example is levels in the kidney and testis, respectively. Both pravastatin, in which exposure of the liver to the drug is SLC22A15 mRNA and SLC22A16 mRNA were also prolonged and adverse eŠects in other tissues are expressed ubiquitously and were expressed at the highest minimized.12,14) Speciˆcally, pravastatin is taken up by levels in the bone marrow. SLC22A17 mRNA was also the liver from the portal vein by SLC21A6 located on expressed ubiquitously and was expressed at the highest the sinusoidal membrane. After exerting its pharmaco- levels in the brain. Similar to the ˆndings of another logicalactionintheliver,pravastatinisthenexcreted study in human subjects,120) SLC22A18 mRNA was into the bile via ABCC2 with only minimal metabolic expressed ubiquitously and was expressed at high levels conversion. The pravastatin released into the duodenum in the colon, kidney, and small intestine. is then reabsorbed by active transport. Therefore, Similar to the ˆndings of another study in the rat,121) e‹cient hepatobiliary transport by SLC21A6 and SLC28A1 mRNA was expressed ubiquitously and was ABCC2, transporters that are expressed speciˆcally in expressed at high levels in the kidney, liver, placenta, the liver (Tables 5, 6), plays an important role in the and small intestine. SLC28A2 mRNA was expressed at enterohepatic circulation, which is responsible for high levels in the small intestine and stomach, with no or maintaining signiˆcant concentrations of this drug in very weak expression in other tissues. Consistent with the liver. Thus, the targeting strategy should focus on the ˆndings of another study in human subjects,122) the diŠerential expression of transporters between the SLC28A3 mRNA was expressed ubiquitously except in target organ and other organs, and the ˆndings of our skeletal muscle and was expressed at high levels in the present study are essential for selecting transporters that bone marrow, pancreas, and trachea. show higher expression levels in the target organ than in Similar to the ˆndings of other studies in human other organs. subjects123) and mammals,124) SLC29A1 mRNA, In our previous studies16,17,127) as well as the present SLC29A2 mRNA, SLC29A3 mRNA, and SLC29A4 study, the TaqMaq method was found to be exquisitely mRNA were expressed ubiquitously and were expressed sensitive, to provide high throughput, to exhibit good at the highest levels in skeletal muscle, skeletal muscle, linearity over a wide range of mRNA concentrations, the placenta, and the spinal cord, respectively. and to permit accurate quantitative evaluation. In the Both SLC36A1 mRNA and SLC36A4 mRNA were present study, total RNA at 25 ng per 50 mLofreaction expressed ubiquitously and were expressed at the highest mixture was used for each tissue. This is in contrast to levels in the bone marrow. SLC36A2 mRNA was existing methods such as Northern blotting, which often expressed at high levels in the kidney and skeletal require 5–20 mg of total RNA. This method could there- muscle, with no expression in other tissues. Consistent fore prove to be particularly useful in studies where the with the ˆndings of another study in the mouse,125) amount of target mRNA is very small, such as studies SLC36A3 mRNA was expressed at high levels in the involving cultured human hepatocytes17–19,128) or clinical testis, with no expression in other tissues. materials129,130) such as blood samples or biopsy speci- SLC38A1 mRNA, SLC38A2 mRNA, SLC38A3 mens. mRNA, SLC38A4 mRNA, SLC38A5 mRNA, and In conclusion, the results of this study provide SLC38A6 mRNA were expressed ubiquitously except in valuable information concerning the tissue-speciˆc peripheral leukocytes for SLC38A3 and were expressed proˆles of mRNA expression of 46 human ABC family at the highest levels in the heart, skeletal muscle, liver, transporters and 108 human SLC family transporters. liver, pancreas, and testis, respectively. The results for These ˆndings should be helpful in studies concerning SLC38A4 were similar to those reported in human the regulation of transport in drug screening systems for subjects.126) new chemical entities in new drug development as well Recent research, including the present study, has as in research related to the clinical diagnosis of disease. identiˆed the ABC and SLC transporters that are In particular, the information obtained in this study is expressed selectively in the liver, kidney, and other expected to be important in assessing the feasibility of organs and has conˆrmed that these transporters may be measuring the mRNA expression levels of target genes a potential target for drug delivery. In particular, the in various tissues. ˆndings of the present study may be useful in selecting transporters that are involved in absorption from the Acknowledgments: The authors would like to thank gastrointestinal tract, elimination by tissues such as the David G. 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