Expression of organic cation transporter 1 (OCT1): unique patterns of indirect regulation by nuclear receptors and hepatospecific gene regulation

References

• Ahlin G, Chen L, Lazorova L, et al. (2011). Genotype-dependent effects of inhibitors of the organic cation transporter, OCT1: Predictions of metformin interactions. Pharmacogenomics J 11:400–411.
   PubMed Web of Science ®Google Scholar
• Ahlin G, Karlsson J, Pedersen JM, et al. (2008). Structural requirements for drug inhibition of the liver specific human organic cation transport protein 1. J Med Chem 51:5932–5942.
   PubMed Web of Science ®Google Scholar
• Angelini S, Soverini S, Ravegnini G, et al. (2013). Association between imatinib transporters and metabolizing enzymes genotype and response in newly diagnosed chronic myeloid leukemia patients receiving imatinib therapy. Haematologica 98:193–200.
   PubMed Web of Science ®Google Scholar
• Aoki M, Terada T, Kajiwara M, et al. (2008). Kidney-specific expression of human organic cation transporter 2 (OCT2/SLC22A2) is regulated by DNA methylation. Am J Physiol Renal Physiol 295:F165–F170.
   PubMed Web of Science ®Google Scholar
• Arimany-Nardi C, Errasti-Murugarren E, Minuesa G, et al. (2014). Nucleoside transporters and human organic cation transporter 1 determine the cellular handling of DNA-methyltransferase inhibitors. Br J Pharmacol 171:3868–3880.
   PubMed Web of Science ®Google Scholar
• Arimany-Nardi CH, Koepsell H, Pastor-Anglada M. (2015). Role of SLC22A1 polymorphic variants in drug disposition, therapeutic responses, and drug–drug interactions. Pharmacogenomics J 15:473–487.
   PubMed Web of Science ®Google Scholar
• Austin G, Holcroft A, Rinne N, et al. (2015). Evidence that the pregnane X and retinoid receptors PXR, RAR and RXR may regulate transcription of the transporter hOCT1 in chronic myeloid leukaemia cells. Eur J Haematol 94:74–78.
   PubMed Web of Science ®Google Scholar
• Badolo L, Bundgaard C, Garmer M, Jensen B. (2013). The role of hepatic transport and metabolism in the interactions between pravastatin or repaglinide and two rOatp inhibitors in rats. Eur J Pharm Sci 49:767–772.
   PubMed Web of Science ®Google Scholar
• Banerjee M, Robbins D, Chen T. (2015). Targeting xenobiotic receptors PXR and CAR in human diseases. Drug Discov Today 20:618–628.
   PubMed Web of Science ®Google Scholar
• Bartel DP. (2004). MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell 116:281–297.
   PubMed Web of Science ®Google Scholar
• Becker ML, Visser LE, Van Schaik RH, et al. (2009). Genetic variation in the organic cation transporter 1 is associated with metformin response in patients with diabetes mellitus. Pharmacogenomics J 9:242–247.
   PubMed Web of Science ®Google Scholar
• Becker ML, Visser LE, Van Schaik RH, et al. (2011). OCT1 polymorphism is associated with response and survival time in anti-Parkinsonian drug users. Neurogenetics 12:79–82.
   PubMed Web of Science ®Google Scholar
• Benoit G, Cooney A, Giguere V, et al. (2006). International Union of Pharmacology. LXVI. Orphan nuclear receptors. Pharmacol Rev 58:798–836.
   PubMed Web of Science ®Google Scholar
• Betel D, Wilson M, Gabow A, et al. (2008). The microRNA.org resource: Targets and expression. Nucleic Acids Res 36:D149–D153.
   PubMed Web of Science ®Google Scholar
• Bexten M, Oswald S, Grube M, et al. (2015). Expression of drug transporters and drug metabolizing enzymes in the bladder urothelium in man and affinity of the bladder spasmolytic trospium chloride to transporters likely involved in its pharmacokinetics. Mol Pharm 12:171–178.
   PubMed Web of Science ®Google Scholar
• Bourdet DL, Pritchard JB, Thakker DR. (2005). Differential substrate and inhibitory activities of ranitidine and famotidine toward human organic cation transporter 1 (hOCT1; SLC22A1), hOCT2 (SLC22A2), and hOCT3 (SLC22A3). J Pharmacol Exp Ther 315:1288–1297.
   PubMed Web of Science ®Google Scholar
• Boxberger KH, Hagenbuch B, Lampe JN. (2014). Common drugs inhibit human organic cation transporter 1 (OCT1)-mediated neurotransmitter uptake. Drug Metab Dispos 42:990–995.
   PubMed Web of Science ®Google Scholar
• Carpaneto A, Koepsell H, Bamberg E, et al. (2010). Sucrose- and H-dependent charge movements associated with the gating of sucrose transporter ZmSUT1. PLoS One 5:e12605.
   PubMed Web of Science ®Google Scholar
• Castell JV, Jover R, Martinez-Jimenez CP, Gomez-Lechon MJ. (2006). Hepatocyte cell lines: Their use, scope and limitations in drug metabolism studies. Expert Opin Drug Metab Toxicol 2:183–212.
   PubMed Web of Science ®Google Scholar
• Chen L, Shu Y, Liang X, et al. (2014). OCT1 is a high-capacity thiamine transporter that regulates hepatic steatosis and is a target of metformin. Proc Natl Acad Sci U S A 111:9983–9988.
   PubMed Web of Science ®Google Scholar
• Chen Y, Tang Y, Guo C, et al. (2012). Nuclear receptors in the multidrug resistance through the regulation of drug-metabolizing enzymes and drug transporters. Biochem Pharmacol 83:1112–1126.
   PubMed Web of Science ®Google Scholar
• Cherrington NJ, Slitt AL, Li N, Klaassen CD. (2004). Lipopolysaccharide-mediated regulation of hepatic transporter mRNA levels in rats. Drug Metab Dispos 32:734–741.
   PubMed Web of Science ®Google Scholar
• Cho SK, Yoon JS, Lee MG, et al. (2011). Rifampin enhances the glucose-lowering effect of metformin and increases OCT1 mRNA levels in healthy participants. Clin Pharmacol Ther 89:416–421.
   PubMed Web of Science ®Google Scholar
• Choi MK, Song IS. (2012). Genetic variants of organic cation transporter 1 (OCT1) and OCT2 significantly reduce lamivudine uptake. Biopharm Drug Dispos 33:170–178.
   PubMed Web of Science ®Google Scholar
• Ciarimboli G, Koepsell H, Iordanova M, et al. (2005). Individual PKC-phosphorylation sites in organic cation transporter 1 determine substrate selectivity and transport regulation. J Am Soc Nephrol 16:1562–1570.
   PubMed Web of Science ®Google Scholar
• Ciarimboli G, Struwe K, Arndt P, et al. (2004). Regulation of the human organic cation transporter hOCT1. J Cell Physiol 201:420–428.
   PubMed Web of Science ®Google Scholar
• Crossman LC, Druker BJ, Deininger MW, et al. (2005). hOCT 1 and resistance to imatinib. Blood 106:1133–1134. author reply 34.
   PubMed Web of Science ®Google Scholar
• Denk GU, Soroka CJ, Mennone A, et al. (2004). Down-regulation of the organic cation transporter 1 of rat liver in obstructive cholestasis. Hepatology 39:1382–1389.
   PubMed Web of Science ®Google Scholar
• Dickens D, Owen A, Alfirevic A, et al. (2012). Lamotrigine is a substrate for OCT1 in brain endothelial cells. Biochem Pharmacol 83:805–814.
   PubMed Web of Science ®Google Scholar
• Dos Santos Pereira JN. (2015). The role of membrane transporters in the pharmacokinetics of psychotropic drugs: In vitro studies with special focus on organic cation transporters-thesis. Gottingen, Germany: Georg-August Universitat, Gottingen.
   Google Scholar
• Dos Santos Pereira JN, Tadjerpisheh S, Abu Abed M, et al. (2014). The poorly membrane permeable antipsychotic drugs amisulpride and sulpiride are substrates of the organic cation transporters from the SLC22 family. AAPS J 16:1247–1258.
   PubMed Web of Science ®Google Scholar
• Eloranta JJ, Jung D, Kullak-Ublick GA. (2006). The human Na+-taurocholate cotransporting polypeptide gene is activated by glucocorticoid receptor and peroxisome proliferator-activated receptor-gamma coactivator-1alpha, and suppressed by bile acids via a small heterodimer partner-dependent mechanism. Mol Endocrinol 20:65–79.
   PubMed Web of Science ®Google Scholar
• Funk C. (2008). The role of hepatic transporters in drug elimination. Expert Opin Drug Metab Toxicol 4:363–379.
   PubMed Web of Science ®Google Scholar
• Gilchrist SE, Alcorn J. (2010). Lactation stage-dependent expression of transporters in rat whole mammary gland and primary mammary epithelial organoids. Fundam Clin Pharmacol 24:205–214.
   PubMed Web of Science ®Google Scholar
• Glaeser H, Bujok K, Schmidt I, et al. (2014). Organic anion transporting polypeptides and organic cation transporter 1 contribute to the cellular uptake of the flavonoid quercetin. Naunyn Schmiedebergs Arch Pharmacol 387:883–891.
   PubMed Web of Science ®Google Scholar
• Godoy P, Lakkapamu S, Schug M, et al. (2010). Dexamethasone-dependent versus -independent markers of epithelial to mesenchymal transition in primary hepatocytes. Biol Chem 391:73–83.
   PubMed Web of Science ®Google Scholar
• Gorboulev V, Ulzheimer JC, Akhoundova A, et al. (1997). Cloning and characterization of two human polyspecific organic cation transporters. DNA Cell Biol 16:871–881.
   PubMed Web of Science ®Google Scholar
• Grinfeld J, Gerrard G, Alikian M, et al. (2013). A common novel splice variant of SLC22A1 (OCT1) is associated with impaired responses to imatinib in patients with chronic myeloid leukaemia. Br J Haematol 163:631–639.
   PubMed Web of Science ®Google Scholar
• Grundemann D, Gorboulev V, Gambaryan S, et al. (1994). Drug excretion mediated by a new prototype of polyspecific transporter. Nature 372:549–552.
   PubMed Web of Science ®Google Scholar
• Grundemann D, Liebich G, Kiefer N, et al. (1999). Selective substrates for non-neuronal monoamine transporters. Mol Pharmacol 56:1–10.
   PubMed Web of Science ®Google Scholar
• Gupta S, Wulf G, Henjakovic M, et al. (2012). Human organic cation transporter 1 is expressed in lymphoma cells and increases susceptibility to irinotecan and paclitaxel. J Pharmacol Exp Ther 341:16–23.
   PubMed Web of Science ®Google Scholar
• Haenisch B, Drescher E, Thiemer L, et al. (2012). Interaction of antidepressant and antipsychotic drugs with the human organic cation transporters hOCT1, hOCT2 and hOCT3. Naunyn Schmiedebergs Arch Pharmacol 385:1017–1023.
   PubMed Web of Science ®Google Scholar
• Han TK, Everett RS, Proctor WR, et al. (2013). Organic cation transporter 1 (OCT1/mOct1) is localized in the apical membrane of Caco-2 cell monolayers and enterocytes. Mol Pharmacol 84:182–189.
   PubMed Web of Science ®Google Scholar
• Hanada K, Nakai K, Tanaka H, et al. (2012). Effect of nuclear receptor downregulation on hepatic expression of cytochrome P450 and transporters in chronic hepatitis C in association with fibrosis development. Drug Metab Pharmacokinet 27:301–306.
   PubMed Web of Science ®Google Scholar
• Hayer-Zillgen M, Bruss M, Bonisch H. (2002). Expression and pharmacological profile of the human organic cation transporters hOCT1, hOCT2 and hOCT3. Br J Pharmacol 136:829–836.
   PubMed Web of Science ®Google Scholar
• Hayer M, Bonisch H, Bruss M. (1999). Molecular cloning, functional characterization and genomic organization of four alternatively spliced isoforms of the human organic cation transporter 1 (hOCT1/SLC22A1). Ann Hum Genet 63:473–482.
   PubMed Web of Science ®Google Scholar
• Heise M, Lautem A, Knapstein J, et al. (2012). Downregulation of organic cation transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) in human hepatocellular carcinoma and their prognostic significance. BMC Cancer 12:109.
   PubMed Web of Science ®Google Scholar
• Hendrickx R, Johansson JG, Lohmann C, et al. (2013). Identification of novel substrates and structure-activity relationship of cellular uptake mediated by human organic cation transporters 1 and 2. J Med Chem 56:7232–7242.
   PubMed Web of Science ®Google Scholar
• Herraez E, Lozano E, Macias RI, et al. (2013). Expression of SLC22A1 variants may affect the response of hepatocellular carcinoma and cholangiocarcinoma to sorafenib. Hepatology 58:1065–1073.
   PubMed Web of Science ®Google Scholar
• Hilgendorf I, Greinix H, Halter JP, et al. (2015). Long-term follow-up after allogeneic stem cell transplantation. Dtsch Arztebl Int 112:51–58.
   PubMed Web of Science ®Google Scholar
• Huber S, Huettner JP, Hacker K, et al. (2015). Esters of bendamustine are by far more potent cytotoxic agents than the parent compound against human sarcoma and carcinoma cells. PLoS One 10:e0133743.
   PubMed Web of Science ®Google Scholar
• Hyrsova L, Smutny T, Carazo A, et al. (2016). The pregnane X receptor down-regulates organic cation transporter 1 (SLC22A1) in human hepatocytes by competing for (“squelching”) SRC-1 coactivator. Br J Pharmacol 173:1703–1715.
   PubMed Web of Science ®Google Scholar
• Ingoglia F, Visigalli R, Rotoli BM, et al. (2015). Functional characterization of the organic cation transporters (OCTs) in human airway pulmonary epithelial cells. Biochim Biophys Acta 1848:1563–1572.
   PubMed Web of Science ®Google Scholar
• Ito N, Ito K, Ikebuchi Y, et al. (2014). Organic cation transporter/solute carrier family 22a is involved in drug transfer into milk in mice. J Pharm Sci 103:3342–3348.
   PubMed Web of Science ®Google Scholar
• Ito S, Kusuhara H, Yokochi M, et al. (2012). Competitive inhibition of the luminal efflux by multidrug and toxin extrusions, but not basolateral uptake by organic cation transporter 2, is the likely mechanism underlying the pharmacokinetic drug-drug interactions caused by cimetidine in the kidney. J Pharmacol Exp Ther 340:393–403.
   PubMed Web of Science ®Google Scholar
• Jang EH, Kim HK, Park CS, Kang JH. (2010). Increased expression of hepatic organic cation transporter 1 and hepatic distribution of metformin in high-fat diet-induced obese mice. Drug Metab Pharmacokinet 25:392–397.
   PubMed Web of Science ®Google Scholar
• Jigorel E, Le Vee M, Boursier-Neyret C, et al. (2006). Differential regulation of sinusoidal and canalicular hepatic drug transporter expression by xenobiotics activating drug-sensing receptors in primary human hepatocytes. Drug Metab Dispos 34:1756–1763.
   PubMed Web of Science ®Google Scholar
• Jonker JW, Schinkel AH. (2004). Pharmacological and physiological functions of the polyspecific organic cation transporters: OCT1, 2, and 3 (SLC22A1-3). J Pharmacol Exp Ther 308:2–9.
   PubMed Web of Science ®Google Scholar
• Jonker JW, Wagenaar E, Mol CA, et al. (2001). Reduced hepatic uptake and intestinal excretion of organic cations in mice with a targeted disruption of the organic cation transporter 1 (Oct1 [Slc22a1]) gene. Mol Cell Biol 21:5471–5477.
   PubMed Web of Science ®Google Scholar
• Jouan E, Le Vee M, Denizot C, et al. (2014). The mitochondrial fluorescent dye rhodamine 123 is a high-affinity substrate for organic cation transporters (OCTs) 1 and 2. Fundam Clin Pharmacol 28:65–77.
   PubMed Web of Science ®Google Scholar
• Jung N, Lehmann C, Rubbert A, et al. (2008). Relevance of the organic cation transporters 1 and 2 for antiretroviral drug therapy in human immunodeficiency virus infection. Drug Metab Dispos 36:1616–1623.
   PubMed Web of Science ®Google Scholar
• Kajiwara M, Terada T, Asaka J, et al. (2008). Regulation of basal core promoter activity of human organic cation transporter 1 (OCT1/SLC22A1). Am J Physiol Gastrointest Liver Physiol 295:G1211–G1216.
   PubMed Web of Science ®Google Scholar
• Kamiyama Y, Matsubara T, Yoshinari K, et al. (2007). Role of human hepatocyte nuclear factor 4alpha in the expression of drug-metabolizing enzymes and transporters in human hepatocytes assessed by use of small interfering RNA. Drug Metab Pharmacokinet 22:287–298.
   PubMed Web of Science ®Google Scholar
• Kato K, Moriyama C, Ito N, et al. (2015). Involvement of organic cation transporters in the clearance and milk secretion of thiamine in mice. Pharm Res 32:2192–2204.
   PubMed Web of Science ®Google Scholar
• Keller T, Egenberger B, Gorboulev V, et al. (2011). The large extracellular loop of organic cation transporter 1 influences substrate affinity and is pivotal for oligomerization. J Biol Chem 286:37874–37886.
   PubMed Web of Science ®Google Scholar
• Kerb R, Brinkmann U, Chatskaia N, et al. (2002). Identification of genetic variations of the human organic cation transporter hOCT1 and their functional consequences. Pharmacogenetics 12:591–595.
   PubMedGoogle Scholar
• Kim MH, Shin HJ, Lim SJ, et al. (2012). Inter-individual variability in OCT1 expression and its relationship with OCT1 genotype in liver samples from a Korean population. Drug Metab Pharmacokinet 27:530–535.
   PubMed Web of Science ®Google Scholar
• Klaassen CD, Aleksunes LM. (2010). Xenobiotic, bile acid, and cholesterol transporters: Function and regulation. Pharmacol Rev 62:1–96.
   PubMed Web of Science ®Google Scholar
• Koehler MR, Wissinger B, Gorboulev V, et al. (1997). The two human organic cation transporter genes SLC22A1 and SLC22A2 are located on chromosome 6q26. Cytogenet Cell Genet 79:198–200.
   PubMedGoogle Scholar
• Koepsell H. (2004). Polyspecific organic cation transporters: Their functions and interactions with drugs. Trends Pharmacol Sci 25:375–381.
   PubMed Web of Science ®Google Scholar
• Koepsell H. (2007). In vivo two-photon fluorescence microscopy opens a new area for investigation of the excretion of cationic drugs in the kidney. Kidney Int 72:387–388.
   PubMed Web of Science ®Google Scholar
• Koepsell H. (2011). Substrate recognition and translocation by polyspecific organic cation transporters. Biol Chem 392:95–101.
   PubMed Web of Science ®Google Scholar
• Koepsell H. (2013a). Polyspecific organic cation transporters and their biomedical relevance in kidney. Curr Opin Nephrol Hypertens 22:533–538.
   PubMed Web of Science ®Google Scholar
• Koepsell H. (2013b). The SLC22 family with transporters of organic cations, anions and zwitterions. Mol Aspects Med 34:413–435.
   PubMed Web of Science ®Google Scholar
• Koepsell H. (2015). Role of organic cation transporters in drug-drug interaction. Expert Opin Drug Metab Toxicol 11:1619–1633.
   PubMed Web of Science ®Google Scholar
• Koepsell H, Lips K, Volk C. (2007). Polyspecific organic cation transporters: structure, function, physiological roles, and biopharmaceutical implications. Pharm Res 24:1227–1251.
   PubMed Web of Science ®Google Scholar
• Kusuhara H, Sekine T, Utsunomiya-Tate N, et al. (1999). Molecular cloning and characterization of a new multispecific organic anion transporter from rat brain. J Biol Chem 274:13675–13680.
   PubMed Web of Science ®Google Scholar
• Kwon M, Choi YA, Choi MK, Song IS. (2015). Organic cation transporter-mediated drug-drug interaction potential between berberine and metformin. Arch Pharm Res 38:849–856.
   PubMed Web of Science ®Google Scholar
• Le Vee M, Jigorel E, Glaise D, et al. (2006). Functional expression of sinusoidal and canalicular hepatic drug transporters in the differentiated human hepatoma HepaRG cell line. Eur J Pharm Sci 28:109–117.
   PubMed Web of Science ®Google Scholar
• Lecureur V, Guillouzo A, Fardel O. (1998). Differential expression of the polyspecific drug transporter OCT1 in rat hepatocarcinoma cells. Cancer Lett 126:227–233.
   PubMed Web of Science ®Google Scholar
• Lee N, Hebert MF, Prasad B, et al. (2013). Effect of gestational age on mRNA and protein expression of polyspecific organic cation transporters during pregnancy. Drug Metab Dispos 41:2225–2232.
   PubMed Web of Science ®Google Scholar
• Lee WK, Reichold M, Edemir B, et al. (2009). Organic cation transporters OCT1, 2, and 3 mediate high-affinity transport of the mutagenic vital dye ethidium in the kidney proximal tubule. Am J Physiol Renal Physiol 296:F1504–F1513.
   PubMed Web of Science ®Google Scholar
• Lee YK, Dell H, Dowhan DH, et al. (2000). The orphan nuclear receptor SHP inhibits hepatocyte nuclear factor 4 and retinoid X receptor transactivation: Two mechanisms for repression. Mol Cell Biol 20:187–195.
   PubMed Web of Science ®Google Scholar
• Li L, Sun S, Weng Y, et al. (2016). Interaction of six protoberberine alkaloids with human organic cation transporters 1, 2 and 3. Xenobiotica 46:175–183.
   PubMed Web of Science ®Google Scholar
• Li L, Tu M, Yang X, et al. (2014). The contribution of human OCT1, OCT3, and CYP3A4 to nitidine chloride-induced hepatocellular toxicity. Drug Metab Dispos 42:1227–1234.
   PubMed Web of Science ®Google Scholar
• Li P, Wang GJ, Robertson TA, Roberts MS. (2009). Liver transporters in hepatic drug disposition: An update. Curr Drug Metab 10:482–498.
   PubMed Web of Science ®Google Scholar
• Li S, Chen Y, Zhang S, et al. (2011). Role of organic cation transporter 1, OCT1 in the pharmacokinetics and toxicity of cis-diammine(pyridine)chloroplatinum(II) and oxaliplatin in mice. Pharm Res 28:610–625.
   PubMed Web of Science ®Google Scholar
• Lin CJ, Tai Y, Huang MT, et al. (2010). Cellular localization of the organic cation transporters, OCT1 and OCT2, in brain microvessel endothelial cells and its implication for MPTP transport across the blood-brain barrier and MPTP-induced dopaminergic toxicity in rodents. J Neurochem 114:717–727.
   PubMed Web of Science ®Google Scholar
• Lips KS, Volk C, Schmitt BM, et al. (2005). Polyspecific cation transporters mediate luminal release of acetylcholine from bronchial epithelium. Am J Respir Cell Mol Biol 33:79–88.
   PubMed Web of Science ®Google Scholar
• Lips KS, Wunsch J, Zarghooni S, et al. (2007). Acetylcholine and molecular components of its synthesis and release machinery in the urothelium. Eur Urol 51:1042–1053.
   PubMed Web of Science ®Google Scholar
• Lozano E, Herraez E, Briz O, et al. (2013). Role of the plasma membrane transporter of organic cations OCT1 and its genetic variants in modern liver pharmacology. Biomed Res Int 2013:692071.
   PubMed Web of Science ®Google Scholar
• Maeda T, Oyabu M, Yotsumoto T, et al. (2007). Effect of pregnane X receptor ligand on pharmacokinetics of substrates of organic cation transporter Oct1 in rats. Drug Metab Dispos 35:1580–1586.
   PubMed Web of Science ®Google Scholar
• Maeda T, Yotsumoto T, Oyabu M, Tamai I. (2008). Effect of glucocorticoid receptor ligand dexamethasone on the expression of organic cation transporter in rat liver. Drug Metab Pharmacokinet 23:67–72.
   PubMed Web of Science ®Google Scholar
• Makishima M, Okamoto AY, Repa JJ, et al. (1999). Identification of a nuclear receptor for bile acids. Science 284:1362–1365.
   PubMed Web of Science ®Google Scholar
• Martinez-Becerra P, Vaquero J, Romero MR, et al. (2012). No correlation between the expression of FXR and genes involved in multidrug resistance phenotype of primary liver tumors. Mol Pharm 9:1693–1704.
   PubMed Web of Science ®Google Scholar
• Matthaei J, Kuron D, Faltraco F, et al. (2015). OCT1 mediates hepatic uptake of sumatriptan and loss-of-function OCT1 polymorphisms affect sumatriptan pharmacokinetics. Clin Pharmacol Ther 99:633–641.
   Web of Science ®Google Scholar
• Meyer-Wentrup F, Karbach U, Gorboulev V, et al. (1998). Membrane localization of the electrogenic cation transporter rOCT1 in rat liver. Biochem Biophys Res Commun 248:673–678.
   PubMed Web of Science ®Google Scholar
• Minematsu T, Giacomini KM. (2011). Interactions of tyrosine kinase inhibitors with organic cation transporters and multidrug and toxic compound extrusion proteins. Mol Cancer Ther 10:531–539.
   PubMed Web of Science ®Google Scholar
• Ming X, Ju W, Wu H, et al. (2009). Transport of dicationic drugs pentamidine and furamidine by human organic cation transporters. Drug Metab Dispos 37:424–430.
   PubMed Web of Science ®Google Scholar
• Minuesa G, Purcet S, Erkizia I, et al. (2008). Expression and functionality of anti-human immunodeficiency virus and anticancer drug uptake transporters in immune cells. J Pharmacol Exp Ther 324:558–567.
   PubMed Web of Science ®Google Scholar
• Misaka S, Knop J, Singer K, et al. (2016). The nonmetabolized beta-blocker nadolol is a substrate of OCT1, OCT2, MATE1, MATE2-K, and P-glycoprotein, but not of OATP1B1 and OATP1B3. Mol Pharm 13:512–519.
   PubMed Web of Science ®Google Scholar
• More SS, Li S, Yee SW, et al. (2010). Organic cation transporters modulate the uptake and cytotoxicity of picoplatin, a third-generation platinum analogue. Mol Cancer Ther 9:1058–1069.
   PubMed Web of Science ®Google Scholar
• Moreno-Navarrete JM, Ortega FJ, Rodriguez-Hermosa JI, et al. (2011). OCT1 expression in adipocytes could contribute to increased metformin action in obese subjects. Diabetes 60:168–176.
   PubMed Web of Science ®Google Scholar
• Moss DM, Liptrott NJ, Siccardi M, Owen A. (2015). Interactions of antiretroviral drugs with the SLC22A1 (OCT1) drug transporter. Front Pharmacol 6:78.
   PubMed Web of Science ®Google Scholar
• Muller J, Lips KS, Metzner L, et al. (2005). Drug specificity and intestinal membrane localization of human organic cation transporters (OCT). Biochem Pharmacol 70:1851–1860.
   PubMed Web of Science ®Google Scholar
• Nakajima M, Yokoi T. (2011). MicroRNAs from biology to future pharmacotherapy: Regulation of cytochrome P450s and nuclear receptors. Pharmacol Ther 131:330–337.
   PubMed Web of Science ®Google Scholar
• Nakanishi T, Haruta T, Shirasaka Y, Tamai I. (2011). Organic cation transporter-mediated renal secretion of ipratropium and tiotropium in rats and humans. Drug Metab Dispos 39:117–122.
   PubMed Web of Science ®Google Scholar
• Namisaki T, Schaeffeler E, Fukui H, et al. (2014). Differential expression of drug uptake and efflux transporters in Japanese patients with hepatocellular carcinoma. Drug Metab Dispos 42:2033–2040.
   PubMed Web of Science ®Google Scholar
• Nie W, Sweetser S, Rinella M, Green RM. (2005). Transcriptional regulation of murine Slc22a1 (Oct1) by peroxisome proliferator agonist receptor-alpha and -gamma. Am J Physiol Gastrointest Liver Physiol 288:G207–G212.
   PubMed Web of Science ®Google Scholar
• Nies AT, Herrmann E, Brom M, Keppler D. (2008). Vectorial transport of the plant alkaloid berberine by double-transfected cells expressing the human organic cation transporter 1 (OCT1, SLC22A1) and the efflux pump MDR1 P-glycoprotein (ABCB1). Naunyn Schmiedebergs Arch Pharmacol 376:449–461.
   PubMed Web of Science ®Google Scholar
• Nies AT, Koepsell H, Winter S, et al. (2009). Expression of organic cation transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) is affected by genetic factors and cholestasis in human liver. Hepatology 50:1227–1240.
   PubMed Web of Science ®Google Scholar
• Nies AT, Schaeffeler E, Van Der Kuip H, et al. (2014). Cellular uptake of imatinib into leukemic cells is independent of human organic cation transporter 1 (OCT1). Clin Cancer Res 20:985–994.
   PubMed Web of Science ®Google Scholar
• Nishimura M, Naito S. (2005). Tissue-specific mRNA expression profiles of human ATP-binding cassette and solute carrier transporter superfamilies. Drug Metab Pharmacokinet 20:452–477.
   PubMedGoogle Scholar
• Onica T, Nichols K, Larin M, et al. (2008). Dexamethasone-mediated up-regulation of human CYP2A6 involves the glucocorticoid receptor and increased binding of hepatic nuclear factor 4 alpha to the proximal promoter. Mol Pharmacol 73:451–460.
   PubMed Web of Science ®Google Scholar
• Parks DJ, Blanchard SG, Bledsoe RK, et al. (1999). Bile acids: Natural ligands for an orphan nuclear receptor. Science 284:1365–1368.
   PubMed Web of Science ®Google Scholar
• Popowski K, Eloranta JJ, Saborowski M, et al. (2005). The human organic anion transporter 2 gene is transactivated by hepatocyte nuclear factor-4 alpha and suppressed by bile acids. Mol Pharmacol 67:1629–1638.
   PubMed Web of Science ®Google Scholar
• Ramamoorthy A, Skaar TC. (2011). In silico identification of microRNAs predicted to regulate the drug metabolizing cytochrome P450 genes. Drug Metab Lett 5:126–131.
   PubMedGoogle Scholar
• Rulcova A, Krausova L, Smutny T, et al. (2013). Glucocorticoid receptor regulates organic cation transporter 1 (OCT1, SLC22A1) expression via HNF4alpha upregulation in primary human hepatocytes. Pharmacol Rep 65:1322–1335.
   PubMed Web of Science ®Google Scholar
• Saadatmand AR. (2012). OCT1-mediated cellular drug uptake and interactions between drug transport and drug metabolism-thesisis. Göttingen, Germany: Georg-August University Göttingen.
   Google Scholar
• Saadatmand AR, Ali R, Brockmoller J, Tzvetkov MV. (2011). Abstract C112: Debrisoquine as a model substrate of the organic cation transporter OCT1. Mol Cancer Ther 10:C112–CC12.
   Google Scholar
• Saborowski M, Kullak-Ublick GA, Eloranta JJ. (2006). The human organic cation transporter-1 gene is transactivated by hepatocyte nuclear factor-4alpha. J Pharmacol Exp Ther 317:778–785.
   PubMed Web of Science ®Google Scholar
• Saini SP, Mu Y, Gong H, et al. (2005). Dual role of orphan nuclear receptor pregnane X receptor in bilirubin detoxification in mice. Hepatology 41:497–505.
   PubMed Web of Science ®Google Scholar
• Sala-Rabanal M, Li DC, Dake GR, et al. (2013). Polyamine transport by the polyspecific organic cation transporters OCT1, OCT2, and OCT3. Mol Pharm 10:1450–1458.
   PubMed Web of Science ®Google Scholar
• Salomon JJ, Hagos Y, Petzke S, et al. (2015). Beta-2 adrenergic agonists are substrates and inhibitors of human organic cation transporter 1. Mol Pharm 12:2633–2641.
   PubMed Web of Science ®Google Scholar
• Sassen S, Miska EA, Caldas C. (2008). MicroRNA: Implications for cancer. Virchows Arch 452:1–10.
   PubMed Web of Science ®Google Scholar
• Seitz T, Stalmann R, Dalila N, et al. (2015). Global genetic analyses reveal strong inter-ethnic variability in the loss of activity of the organic cation transporter OCT1. Genome Med 7:56.
   PubMed Web of Science ®Google Scholar
• Seol W, Choi HS, Moore DD. (1996). An orphan nuclear hormone receptor that lacks a DNA binding domain and heterodimerizes with other receptors. Science 272:1336–1339.
   PubMed Web of Science ®Google Scholar
• Shu Y, Brown C, Castro RA, et al. (2008). Effect of genetic variation in the organic cation transporter 1, OCT1, on metformin pharmacokinetics. Clin Pharmacol Ther 83:273–280.
   PubMed Web of Science ®Google Scholar
• Shu Y, Sheardown SA, Brown C, et al. (2007). Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action. J Clin Invest 117:1422–1431.
   PubMed Web of Science ®Google Scholar
• Schaeffeler E, Hellerbrand C, Nies AT, et al. (2011). DNA methylation is associated with downregulation of the organic cation transporter OCT1 (SLC22A1) in human hepatocellular carcinoma. Genome Med 3:82.
   PubMed Web of Science ®Google Scholar
• Sladek FM, Zhong WM, Lai E, Darnell JE Jr. (1990). Liver-enriched transcription factor HNF-4 is a novel member of the steroid hormone receptor superfamily. Genes Dev 4:2353–2365.
   PubMed Web of Science ®Google Scholar
• Smutny T, Duintjer Tebbens J, Pavek P. (2015). Bioinformatic analysis of miRNAs targeting the key nuclear receptors regulating CYP3A4 gene expression: The challenge of the CYP3A4 ‘‘missing heritability’’ enigma. J Appl Biomed 13:181–188.
   Web of Science ®Google Scholar
• Smutny T, Mani S, Pavek P. (2013). Post-translational and post-transcriptional modifications of pregnane X receptor (PXR) in regulation of the cytochrome P450 superfamily. Curr Drug Metab 14:1059–1069.
   PubMed Web of Science ®Google Scholar
• Sogame Y, Kitamura A, Yabuki M, Komuro S. (2009). A comparison of uptake of metformin and phenformin mediated by hOCT1 in human hepatocytes. Biopharm Drug Dispos 30:476–484.
   PubMed Web of Science ®Google Scholar
• Swift B, Nebot N, Lee JK, et al. (2013). Sorafenib hepatobiliary disposition: Mechanisms of hepatic uptake and disposition of generated metabolites. Drug Metab Dispos 41:1179–1186.
   PubMed Web of Science ®Google Scholar
• Takayama K, Kawabata K, Nagamoto Y, et al. (2013). 3D spheroid culture of hESC/hiPSC-derived hepatocyte-like cells for drug toxicity testing. Biomaterials 34:1781–1789.
   PubMed Web of Science ®Google Scholar
• Tu M, Sun S, Wang K, et al. (2013). Organic cation transporter 1 mediates the uptake of monocrotaline and plays an important role in its hepatotoxicity. Toxicology 311:225–230.
   PubMed Web of Science ®Google Scholar
• Tzvetkov MV, Dos Santos Pereira JN, Meineke I, et al. (2013). Morphine is a substrate of the organic cation transporter OCT1 and polymorphisms in OCT1 gene affect morphine pharmacokinetics after codeine administration. Biochem Pharmacol 86:666–678.
   PubMed Web of Science ®Google Scholar
• Tzvetkov MV, Saadatmand AR, Bokelmann K, et al. (2012). Effects of OCT1 polymorphisms on the cellular uptake, plasma concentrations and efficacy of the 5-HT(3) antagonists tropisetron and ondansetron. Pharmacogenomics J 12:22–29.
   PubMed Web of Science ®Google Scholar
• Tzvetkov MV, Saadatmand AR, Lotsch J, et al. (2011). Genetically polymorphic OCT1: Another piece in the puzzle of the variable pharmacokinetics and pharmacodynamics of the opioidergic drug tramadol. Clin Pharmacol Ther 90:143–150.
   PubMed Web of Science ®Google Scholar
• Tzvetkov MV, Vormfelde SV, Balen D, et al. (2009). The effects of genetic polymorphisms in the organic cation transporters OCT1, OCT2, and OCT3 on the renal clearance of metformin. Clin Pharmacol Ther 86:299–306.
   PubMed Web of Science ®Google Scholar
• Umehara KI, Iwatsubo T, Noguchi K, Kamimura H. (2007). Functional involvement of organic cation transporter1 (OCT1/Oct1) in the hepatic uptake of organic cations in humans and rats. Xenobiotica 37:818–831.
   PubMed Web of Science ®Google Scholar
• Umehara KI, Iwatsubo T, Noguchi K, et al. (2008). Effect of cationic drugs on the transporting activity of human and rat OCT/Oct 1-3 in vitro and implications for drug-drug interactions. Xenobiotica 38:1203–1218.
   PubMed Web of Science ®Google Scholar
• Venkatesh M, Mukherjee S, Wang H, et al. (2014). Symbiotic bacterial metabolites regulate gastrointestinal barrier function via the xenobiotic sensor PXR and Toll-like receptor 4. Immunity 41:296–310.
   PubMed Web of Science ®Google Scholar
• Vrzal R, Stejskalova L, Monostory K, et al. (2009). Dexamethasone controls aryl hydrocarbon receptor (AhR)-mediated CYP1A1 and CYP1A2 expression and activity in primary cultures of human hepatocytes. Chem Biol Interact 179:288–296.
   PubMed Web of Science ®Google Scholar
• Wang DS, Jonker JW, Kato Y, et al. (2002). Involvement of organic cation transporter 1 in hepatic and intestinal distribution of metformin. J Pharmacol Exp Ther 302:510–515.
   PubMed Web of Science ®Google Scholar
• Wang DS, Kusuhara H, Kato Y, et al. (2003). Involvement of organic cation transporter 1 in the lactic acidosis caused by metformin. Mol Pharmacol 63:844–848.
   PubMed Web of Science ®Google Scholar
• Watt AJ, Garrison WD, Duncan SA. (2003). HNF4: A central regulator of hepatocyte differentiation and function. Hepatology 37:1249–1253.
   PubMed Web of Science ®Google Scholar
• Wilczynska A, Bushell M. (2015). The complexity of miRNA-mediated repression. Cell Death Differ 22:22–33.
   PubMed Web of Science ®Google Scholar
• Wong N, Wang X. (2015). miRDB: An online resource for microRNA target prediction and functional annotations. Nucleic Acids Res 43:D146–D152.
   PubMed Web of Science ®Google Scholar
• Yamagata K, Furuta H, Oda N, et al. (1996). Mutations in the hepatocyte nuclear factor-4alpha gene in maturity-onset diabetes of the young (MODY1). Nature 384:458–460.
   PubMed Web of Science ®Google Scholar
• Yasujima T, Ohta K, Inoue K, Yuasa H. (2011). Characterization of human OCT1-mediated transport of DAPI as a fluorescent probe substrate. J Pharm Sci 100:4006–4012.
   PubMed Web of Science ®Google Scholar
• Yin J, Duan H, Shirasaka Y, et al. (2015). Atenolol renal secretion is mediated by human organic cation transporter 2 and multidrug and toxin extrusion proteins. Drug Metab Dispos 43:1872–1881.
   PubMed Web of Science ®Google Scholar
• Yonezawa A, Masuda S, Yokoo S, et al. (2006). Cisplatin and oxaliplatin, but not carboplatin and nedaplatin, are substrates for human organic cation transporters (SLC22A1-3 and multidrug and toxin extrusion family). J Pharmacol Exp Ther 319:879–886.
   PubMed Web of Science ®Google Scholar
• Yu AM, Tian Y, Tu MJ, et al. (2015). MicroRNA Pharmacoepigenetics: Posttranscriptional regulation mechanisms behind variable drug disposition and strategy to develop more effective therapy. Drug Metab Dispos 44:308–319.
   Web of Science ®Google Scholar
• Zeeh D, Harrach S, Fischer M, et al. (2013). Interaction of murine and human organic cation transporters with tyrosine kinase inhibitors and platin derivatives. Proceedings of The Physiological Society. Birmingham, United Kingdom.
   Google Scholar
• Zhang L, Dresser MJ, Gray AT, et al. (1997). Cloning and functional expression of a human liver organic cation transporter. Mol Pharmacol 51:913–921.
   PubMed Web of Science ®Google Scholar
• Zhang L, Gorset W, Washington CB, et al. (2000). Interactions of HIV protease inhibitors with a human organic cation transporter in a mammalian expression system. Drug Metab Dispos 28:329–334.
   PubMed Web of Science ®Google Scholar
• Zhang T, Xiang CD, Gale D, et al. (2008). Drug transporter and cytochrome P450 mRNA expression in human ocular barriers: Implications for ocular drug disposition. Drug Metab Dispos 36:1300–1307.
   PubMed Web of Science ®Google Scholar