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Role of SLC22A1 Polymorphic Variants in Drug Disposition, Therapeutic Responses, and Drug–Drug Interactions

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Role of SLC22A1 Polymorphic Variants in Drug Disposition, Therapeutic Responses, and Drug–Drug Interactions The Pharmacogenomics Journal (2015) 15, 473–487 © 2015 Macmillan Publishers Limited All rights reserved 1470-269X/15 www.nature.com/tpj REVIEW Role of SLC22A1 polymorphic variants in drug disposition, therapeutic responses, and drug–drug interactions C Arimany-Nardi1, H Koepsell2 and M Pastor-Anglada1 The SCL22A1 gene encodes the broad selectivity transporter hOCT1. hOCT1 is expressed in most epithelial barriers thereby contributing to drug pharmacokinetics. It is also expressed in different drug target cells, including immune system cells and others. Thus, this membrane protein might also contribute to drug pharmacodynamics. Up to 1000 hOCT1 polymorphisms have been identified so far, although only a small fraction of those have been mechanistically studied. A paradigm in the field of drug transporter pharmacogenetics is the impact of hOCT1 gene variability on metformin clinical parameters, affecting area under the concentration–time curve, Cmax and responsiveness. However, hOCT1 also mediates the translocation of a variety of drugs used as anticancer, antiviral, anti-inflammatory, antiemetic agents as well as drugs used in the treatment of neurological diseases among. This review focuses exclusively on those drugs for which some pharmacogenetic data are available, and aims at highlighting the need for further clinical research in this area. The Pharmacogenomics Journal (2015) 15, 473–487; doi:10.1038/tpj.2015.78; published online 3 November 2015 SLC22 GENE FAMILY HOCT1 The SLC22 gene family encodes for more than 30 proteins, some The first organic cation transporter (rOCT) was cloned from rat of them acting as organic cation transporters (OCTs), organic kidney in 1994.4 Some years later the mouse (mOCT1)5 and rabbit cation and zwitterion transporters (OCTNs) and organic anion orthologues (rbOCT1)6 were isolated. hOCT1 was independently transporters (OATs). OCTs, OCTNs and organic anion transporters, cloned by two groups.7,8 A difference between both human show broad substrate selectivity, being able to transport multiple complementary DNA clones resulting in three amino-acid compounds different in size and structure. substitutions was observed being the human orthologue 78% identical to rOCT1.9 hOCT1 is encoded by the SLC22A1 gene, which contains 11 exons and 10 introns localised on chromo- HUMAN ORGANIC CATION TRANSPORTERS (HOCTS) some 6.q26-7. 10 Although OCT1 is highly conserved in mammals, Organic cation transporters (OCT1-3), such as many transporters in only a few amino acids are also conserved in fish, Drosophila the SLC22 family, have a predicted membrane topology of melanogaster or Caenorhabditis elegans (Figure 1). 12 α-helical transmembrane domains (TMDs), an intracellular N OCT1 protein is expressed mostly in epithelial cells. Regarding terminus, a large glycosylated extracellular loop between TMDs 1 its tissue distribution, hOCT1 is mainly expressed in the liver, and 2, a large intracellular loop with phosphorylation sites where it is located at the sinusoidal membrane of the between TMDs 6 and 7 and an intracellular C terminus. OCTs hepatocytes.11 OCT1 orthologues in rat, mouse and rabbit are are equilibrative transporters. Translocation of cations by these also expressed strongly in kidney, although SLC22A1 messenger transporters is also electrogenic. Thus, the membrane potential RNA abundance in human renal tissue appears to be low.10,12 might serve as a driving force in addition to the concentration Nevertheless, the OCT1 protein has been identified although gradient. They can translocate a broad variety of substrates with differentially localized in rat (basolateral membrane of proximal highly variable molecular structures, and similarly, they can also be tubules),10 and human kidneys (localised at the apical and inhibited by a large number of compounds, which are able to subapical domains of both proximal and distal tubules).12 interact with the transporters without being translocated. OCTs hOCT1 is also expressed in many other organs including small are potentially bidirectional transporters able to interact with intestine, at the brush border membrane; lung, at the luminal inhibitors with different affinities depending on the site of drug– membrane of bronchial epithelial cells; heart; skeletal muscle; transporter interaction.1 OCT substrates include endogenous compounds, drugs, xeno- brain, in endothelial cells of microvessels; placenta; mammary gland; adrenal gland; eye, in cornea, iris–ciliary body and blood– biotics as well as a variety of model substrates, which are routinely 10,13–20 used for OCT function assays. Most substrates and inhibitors retina barrier; adipose tissue; and immune cells (Table 1). of OCTs broadly overlap among the different members of the hOCT1 expression in tumours has also been broadly 10,21–23 family.2,3 reported, although in some cases its expression levels 1Molecular Physiology and Experimental Therapeutics, Department of Biochemistry and Molecular Biology, Institute of Biomedicine (IBUB), University of Barcelona and Oncology Program, National Biomedical Research Institute on Liver and Gastrointestinal Diseases (CIBER EHD), Instituto de Salud Carlos III, Barcelona, Spain and 2Department of Molecular Plant Physiology and Biophysics, Julius-von-Sachs-Institute, University Würzburg, Würzburg, Germany. Correspondence: Professor M Pastor-Anglada, Departament de Bioquímica i Biologia Molecular, Universitat de Barcelona, Avinguda Diagonal 643, Barcelona 08028, Spain. E-mail: [email protected] Received 5 February 2015; revised 20 August 2015; accepted 8 September 2015; published online 3 November 2015 Drug pharmacogenetics and SLC22A1 polymorphisms C Arimany-Nardi et al 474 may be downregulated when compared with surrounding normal bases and some non-charged compounds. Substrates of human tissue, as recently shown for liver cancer.24 OCT1 include model cations, endogenous compounds and drugs In summary, the anatomical distribution of hOCT1 in most among others. Some of the model compounds used to asses epithelial barriers anticipates a major role for this membrane hOCT1 activity are tetraethylammonium, 1-methyl-4-phenyl- transporter in controlling drug pharmacokinetics and, eventually, pyridinium and 4-[4-(dimthylamino)-styryl]-N-methylpyridinium. pharmacodynamics. hOCT1 was originally included in the first set Endogenous compounds transported by human OCT1 include of human transporters relevant to drug development by the choline, acetylcholine, the neuromodulators histidyl-proline dike- 25 International Transporter Consortium. topiperazine (cyclo(His-Pro)) and salsolinol, the L-arginine meta- Human OCT1 can transport not only monovalent organic bolite agmatine, the polyamine putrescine and vitamine B1.10,26–28 cations, but also some divalent organic cations, some weak Drugs transported by hOCT1 include metformin, used for the B. taurus ----------------------MLTVDDVLEQVGEFGWFQKQTFLILCLLSAAFAPIYVG 38 C. elegans MSFQAMETFAEISQEILMSATKPPDFDFVLEQVGNYGTYQIVFFFIICLPTSLPSAFSAF 60 D. melanogaster -----------------------MGYDDVITHLGEFGPYQKRIYYLLCLP-AIVCAFHKL 36 H. sapiens ----------------------MPTVDDILEQVGESGWFQKQAFLILCLLSAAFAPICVG 38 M. musculus ----------------------MPTVDDVLEHVGEFGWFQKQAFLLLCLISASLAPIYVG 38 R. norvegicus ----------------------MPTVDDVLEQVGEFGWFQKQAFLLLCLISASLAPIYVG 38 S. salar -----------------------MGFADLLNDVGGFGRFQWIHVTLLSIPGLLMASQNLL 37 S. enterica ------------------------------------------------------------ B. taurus -IVFLAFTPDHRCRSPGVAELSRRCGWSLAEELNYTVPGPGPE------SQCLRYEVDWN 91 C. elegans NIPFVVGNPPHTCHIP--------EGKEYLRPLTNDTQILSCK------------QYNET 100 D. melanogaster AGVFLLAKPDFRCALP--------YENGSIYELSPHLWNLSYP------------ENERC 76 H. sapiens -IVFLGFTPDHHCQSPGVAELSQRCGWSPAEELNYTVPGLGPAGEA-FLGQCRRYEVDWN 96 M. musculus -IVFLGFTPDHHCRSPGVAELSQRCGWSPAEELNYTVPGLGSAGEASFLSQCMKYEVDWN 97 R. norvegicus -IVFLGFTPGHYCQNPGVAELSQRCGWSQAEELNYTVPGLGPSDEASFLSQCMRYEVDWN 97 S. salar -NNFTAGMPGHHCTIPNRTSIASSQNISQSEVDDRELLRAFIPMDASGTKLSKCTRYVEA 96 S. enterica ------------------------------------------------------MEDNDH 6 B. taurus QSTLGCLDPLAS-LATNGSPLPLGPCEQGWVYDTP--GSSIVTEFNLVCDDSWKVDLFQS 148 C. elegans QINVFRAFTSAP-VDTYSDRISLVPCQNGWDYDNSTYLDSLVTEFNLVCDQQAWIEISTT 159 D. melanogaster SYYDVDYTEEYL-NGSIPRSSNETKTCSSYVYDRSKYLNSAVTEWNLVCSRSLLSATSDS 135 H. sapiens QSALSCVDPLAS-LATNRSHLPLGPCQDGWVYDTP--GSSIVTEFNLVCADSWKLDLFQS 153 M. musculus QSTLDCVDPLSS-LAANRSHLPLSPCEHGWVYDTP--GSSIVTEFNLVCGDAWKVDLFQS 154 R. norvegicus QSTLDCVDPLSS-LVANRSQLPLGPCEHGWVYDTP--GSSIVTEFNLVCGDAWKVDLFQS 154 S. salar QWHLLESNVSVIGHQANFSKLETEICLDGWTYDKTEFLSTVVSEWDLVCTLRPMKQMSQT 156 S. enterica IGARLDRLPLSRFHFRIFGIISFGLLLTGFLSYSG--NVVLAKLINNGWSNNYLNAAFTS 64 B. taurus CVNLGFFLGSLGVGYIADRFGRKVCLLATTLTCASLGVLTAVAPDYTSLLIFRLLQGLVS 208 C. elegans SFYVGSFIGNCLFGYVADKFGRRRSFFVILTVLIVCGTASSFAKDIESFIILRFFTGLAF 219 D. melanogaster LFMLGVLLGSFIFGQMSDKLGRKPTFFASLVLQLIFGVLAAVAPEYFSYTISRMIVGATT 195 H. sapiens CLNAGFLFGSLGVGYFADRFGRKLCLLGTVLVNAVSGVLMAFSPNYMSMLLFRLLQGLVS 213 M. musculus CVNLGFFLGSLVVGYIADRFGRKLCLLVTTLVTSLSGVLTAVAPDYTSMLLFRLLQGMVS 214 R. norvegicus CVNLGFFLGSLVVGYIADRFGRKLCLLVTTLVTSVSGVLTAVAPDYTSMLLFRLLQGMVS 214 S. salar IYMGGVLAGAIIFGGLSDRFGRKALLIWSYFQLATLGTCTAFSPSFMTYCIFRFMTGMAV 216 S. enterica ALMLGYFIGSLTGGFIGDYLGRRKAFRINLLLVGISATAAAFVPNMYWLIFFRCLMGTGM 124 B. taurus KGSWTAGYTLITEFVGLGYRRTVAILYQMAFTVGLVLLSGLAYILPHWRWLQLAVSLP-- 266 C. elegans PALFQIPFIICMEFMGNSGRIFSGLMTSLFFGAAMALLGVVAMFIRRWRQLTFFCNAP-- 277 D. melanogaster SGVFLVAYVIALEMVGSSYRLFAGVAMQMFFSVGFMLTAGFAYFIHDWRWLQIAITLP-- 253 H. sapiens KGNWMAGYTLITEFVGSGSRRTVAIMYQMAFTVGLVALTGLAYALPHWRWLQLAVSLP--
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