Targeted disruption of organic cation transporter 3 attenuates the pharmacologic response to metformin

Molecular Pharmacology

Volumn 88, Issue 1, 2015, Pages 75-83

  Chen, Eugene C ^a   Liang, Xiaomin ^a   Yee, Sook Wah ^a   Geier, Ethan G ^a,c   Stocker, Sophie L ^a,d   Chen, Ligong ^b   Giacomini, Kathleen M ^a  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b Tsinghua University   (China)

^c Apricity Therapeutics   (United States)

^d GLAXOSMITHKLINE   (Australia)

Author keywords

[No Author keywords available]

Indexed keywords

GLUCOSE; GLUCOSE TRANSPORTER 4; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE KINASE; MESSENGER RNA; METFORMIN; ORGANIC CATION TRANSPORTER 3; 3' UNTRANSLATED REGION; ANTIDIABETIC AGENT; ORGANIC CATION TRANSPORTER; SOLUTE CARRIER FAMILY 22 (ORGANIC CATION TRANSPORTER), MEMBER 3;

3' UNTRANSLATED REGION; ADIPOSE TISSUE; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL TISSUE; AREA UNDER THE CURVE; ARTICLE; BIOACCUMULATION; CELL DISRUPTION; COMPARATIVE STUDY; DRUG ABSORPTION; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG CLEARANCE; DRUG EFFECT; DRUG ELIMINATION; DRUG TISSUE LEVEL; ENZYME PHOSPHORYLATION; GENETIC POLYMORPHISM; GLUCOSE BLOOD LEVEL; HUMAN; HUMAN CELL; KINETIC PARAMETERS; KNOCKOUT MOUSE; MALE; MAXIMUM PLASMA CONCENTRATION; MOUSE; NONHUMAN; NORMAL HUMAN; ORAL GLUCOSE TOLERANCE TEST; PLASMA CONCENTRATION-TIME CURVE; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN TARGETING; REAL TIME POLYMERASE CHAIN REACTION; REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION; SKELETAL MUSCLE; TISSUE DISTRIBUTION; VOLUME OF DISTRIBUTION; WESTERN BLOTTING; WILD TYPE MOUSE; ANIMAL; BIOAVAILABILITY; DRUG EFFECTS; GENE EXPRESSION REGULATION; GENETICS; HCT116 CELL LINE; HEPG2 CELL LINE; INTRAPERITONEAL DRUG ADMINISTRATION; METABOLISM; SINGLE NUCLEOTIDE POLYMORPHISM; TUMOR CELL LINE;

3' UNTRANSLATED REGIONS; ADIPOSE TISSUE; ANIMALS; BIOLOGICAL AVAILABILITY; CELL LINE, TUMOR; GENE EXPRESSION REGULATION; GLUCOSE; HCT116 CELLS; HEALTHY VOLUNTEERS; HEP G2 CELLS; HUMANS; HYPOGLYCEMIC AGENTS; INJECTIONS, INTRAPERITONEAL; MALE; METFORMIN; MICE; MICE, KNOCKOUT; MUSCLE, SKELETAL; ORGANIC CATION TRANSPORT PROTEINS; POLYMORPHISM, SINGLE NUCLEOTIDE; TISSUE DISTRIBUTION;

EID: 84940200906     PISSN: 0026895X     EISSN: 15210111     Source Type: Journal    
DOI: 10.1124/mol.114.096776     Document Type: Article

References (34)

1. Becker ML, Visser LE, van Schaik RHN, Hofman A, Uitterlinden AG, and Stricker BHC (2009) Genetic variation in the multidrug and toxin extrusion 1 transporter protein influences the glucose-lowering effect of metformin in patients with diabetes: a preliminary study. Diabetes 58:745-749.
2. Bleasby K, Castle JC, Roberts CJ, Cheng C, Bailey WJ, Sina JF, Kulkarni AV, Hafey MJ, Evers R, and Johnson JM et al. (2006) Expression profiles of 50 xenobiotic transporter genes in humans and pre-clinical species: a resource for investigations into drug disposition. Xenobiotica 36:963-988.
3. Boyle JG, Salt IP, and McKay GA (2010) Metformin action on AMP-activated protein kinase: a translational research approach to understanding a potential new therapeutic target. Diabet Med 27:1097-1106.
4. Centers for Disease Control and Prevention (2014) National Diabetes Statistics Report: Estimates of Diabetes and Its Burden in the United States, 2014, US Department of Health and Human Services, Atlanta, GA.
5. Chen L, Pawlikowski B, Schlessinger A, More SS, Stryke D, Johns SJ, Portman MA, Chen E, Ferrin TE, and Sali A et al. (2010) Role of organic cation transporter 3 (SLC22A3) and its missense variants in the pharmacologic action of metformin. Pharmacogenet Genomics 20:687-699.
6. Chen L, Shu Y, Liang X, Chen EC, Yee SW, Zur AA, Li S, Xu L, Keshari KR, and Lin MJ et al. (2014) OCT1 is a high-capacity thiamine transporter that regulates hepatic steatosis and is a target of metformin. Proc Natl Acad Sci USA 111:9983-9988.
7. Chen Y, Li S, Brown C, Cheatham S, Castro RA, Leabman MK, Urban TJ, Chen L, Yee SW, and Choi JH et al. (2009) Effect of genetic variation in the organic cation transporter 2 on the renal elimination of metformin. Pharmacogenet Genomics 19:497-504.
8. Choi JH, Yee SW, Ramirez AH, Morrissey KM, Jang GH, Joski PJ, Mefford JA, Hesselson SE, Schlessinger A, and Jenkins G et al. (2011) A common 5′-UTR variant in MATE2-K is associated with poor response to metformin. Clin Pharmacol Ther 90:674-684.
9. Goswami S, Yee SW, Stocker S, Mosley JD, Kubo M, Castro R, Mefford JA, Wen C, Liang X, and Witte J et al. (2014) Genetic variants in transcription factors are associated with the pharmacokinetics and pharmacodynamics of metformin. Clin Pharmacol Ther 96:370-379.
10. Graham GG, Punt J, Arora M, Day RO, Doogue MP, Duong JK, Furlong TJ, Greenfield JR, Greenup LC, and Kirkpatrick CM et al. (2011) Clinical pharmacokinetics of metformin. Clin Pharmacokinet 50:81-98.
11. Grundberg E, Small KS, Hedman ÅK, Nica AC, Buil A, Keildson S, Bell JT, Yang T-P, Meduri E, and Barrett A et al.; Multiple Tissue Human Expression Resource (MuTHER) Consortium (2012) Mapping cis- and trans-regulatory effects across multiple tissues in twins. Nat Genet 44:1084-1089.
12. Higgins JW, Bedwell DW, and Zamek-Gliszczynski MJ (2012) Ablation of both organic cation transporter (OCT)1 and OCT2 alters metformin pharmacokinetics but has no effect on tissue drug exposure and pharmacodynamics. Drug Metab Dispos 40:1170-1177.
13. Horton RE, Apple DM, Owens WA, Baganz NL, Cano S, Mitchell NC, Vitela M, Gould GG, Koek W, and Daws LC (2013) Decynium-22 enhances SSRI-induced antidepressant-like effects in mice: uncovering novel targets to treat depression. J Neurosci 33:10534-10543.
14. Jonker JW and 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.
15. Jonker JW, Wagenaar E, Mol CA, Buitelaar M, Koepsell H, Smit JW, and Schinkel AH (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.
16. Jonker JW, Wagenaar E, Van Eijl S, and Schinkel AH (2003) Deficiency in the organic cation transporters 1 and 2 (Oct1/Oct2 [Slc22a1/Slc22a2]) in mice abolishes renal secretion of organic cations. Mol Cell Biol 23:7902-7908.
17. Kirpichnikov D, McFarlane SI, and Sowers JR (2002) Metformin: an update. Ann Intern Med 137:25-33.
18. Koepsell H (2004) Polyspecific organic cation transporters: their functions and interactions with drugs. Trends Pharmacol Sci 25:375-381.
19. Koepsell H, Schmitt BM, and Gorboulev V (2003) Organic cation transporters. Rev Physiol Biochem Pharmacol 150:36-90.
20. Lee N, Duan H, Hebert MF, Liang CJ, Rice KM, and Wang J (2014) Taste of a pill: organic cation transporter-3 (OCT3) mediates metformin accumulation and secretion in salivary glands. J Biol Chem 289:27055-27064.
21. Müller J, Lips KS, Metzner L, Neubert RHH, Koepsell H, and Brandsch M (2005) Drug specificity and intestinal membrane localization of human organic cation transporters (OCT). Biochem Pharmacol 70:1851-1860.
22. Pernicova I and Korbonits M (2014) Metformin - mode of action and clinical implications for diabetes and cancer. Nat Rev Endocrinol 10:143-156.
23. th ed. Wolters Kluwer Health/Lippincott William & Wilkins, Philadelphia, PA.
24. Shu Y, Sheardown SA, Brown C, Owen RP, Zhang S, Castro RA, Ianculescu AG, Yue L, Lo JC, and Burchard EG et al. (2007) Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action. J Clin Invest 117:1422-1431.
25. Somogyi A and Muirhead M (1987) Pharmacokinetic interactions of cimetidine 1987. Clin Pharmacokinet 12:321-366.
26. Somogyi A, Stockley C, Keal J, Rolan P, and Bochner F (1987) Reduction of metformin renal tubular secretion by cimetidine in man. Br J Clin Pharmacol 23:545-551.
27. Song IS, Shin HJ, Shim EJ, Jung IS, Kim WY, Shon JH, and Shin JG (2008) Genetic variants of the organic cation transporter 2 influence the disposition of metformin. Clin Pharmacol Ther 84:559-562.
28. Stocker SL, Morrissey KM, Yee SW, Castro RA, Xu L, Dahlin A, Ramirez AH, Roden DM, Wilke RA, and McCarty CA et al. (2013) The effect of novel promoter variants in MATE1 and MATE2 on the pharmacokinetics and pharmacodynamics of metformin. Clin Pharmacol Ther 93:186-194.
29. Tsuda M, Terada T, Mizuno T, Katsura T, Shimakura J, and Inui K (2009) Targeted disruption of the multidrug and toxin extrusion 1 (mate1) gene in mice reduces renal secretion of metformin. Mol Pharmacol 75:1280-1286.
30. Vialou V, Balasse L, Callebert J, Launay J-M, Giros B, and Gautron S (2008) Altered aminergic neurotransmission in the brain of organic cation transporter 3-deficient mice. J Neurochem 106:1471-1482.
31. Wang DS, Jonker JW, Kato Y, Kusuhara H, Schinkel AH, and Sugiyama Y (2002) Involvement of organic cation transporter 1 in hepatic and intestinal distribution of metformin. J Pharmacol Exp Ther 302:510-515.
32. Wultsch T, Grimberg G, Schmitt A, Painsipp E, Wetzstein H, Breitenkamp AFS, Gründemann D, Schömig E, Lesch K-P, and Gerlach M et al. (2009) Decreased anxiety in mice lacking the organic cation transporter 3. J Neural Transm 116:689-697.
33. Zhu H-J, Appel DI, Gründemann D, and Markowitz JS (2010) Interaction of organic cation transporter 3 (SLC22A3) and amphetamine. J Neurochem 114:142-149.
34. Zwart R, Verhaagh S, Buitelaar M, Popp-Snijders C, and Barlow DP (2001) Impaired activity of the extraneuronal monoamine transporter system known as uptake-2 in Orct3/Slc22a3-deficient mice. Mol Cell Biol 21:4188-4196 Am Soc Microbiol.