Uptake of cardiovascular drugs into the human heart: Expression, regulation, and function of the carnitine transporter OCTN2 (SLC22A5)

Circulation

Volumn 113, Issue 8, 2006, Pages 1114-1122

  Grube, Markus ^a   Meyer Zu Schwabedissen, Henriette E U ^a   Präger, Damaris ^a   Haney, Jeanette ^a   Möritz, Klaus Uwe ^a   Meissner, Konrad ^a   Rosskopf, Dieter ^a   Eckel, Lothar ^b   Böhm, Michael ^c   Jedlitschky, Gabriele ^a   Kroemer, Heyo K ^a,d  

^a UNIVERSITY OF GREIFSWALD   (Germany)

^b Klinikum Karlsburg   (Germany)

^c SAARLAND UNIVERSITY   (Germany)

^d Department of Pharmacology ^*  (Germany)

Author keywords

Carnitine; Drug transport; Organic cation transport proteins; Pharmacology

Indexed keywords

ABC TRANSPORTER; ACEBUTOLOL; ACETYLSALICYLIC ACID; BETA ADRENERGIC RECEPTOR BLOCKING AGENT; BISOPROLOL; CALCIUM CHANNEL BLOCKING AGENT; CANRENOIC ACID; CAPTOPRIL; CARNITINE TRANSPORTER; CARVEDILOL; CLOPIDOGREL; CORTISONE; DIGOXIN; DIPEPTIDYL CARBOXYPEPTIDASE INHIBITOR; ENALAPRIL; GLYCOPROTEIN P; LIDOCAINE; MEMANTINE; MESSENGER RNA; METOPROLOL; MILDRONATE; MULTIDRUG RESISTANCE PROTEIN 1; ORGANIC CATION TRANSPORTER 2; PROPRANOLOL; PROTEIN SLC22A5; SPIRONOLACTONE; TALINOLOL; TICLOPIDINE; UNCLASSIFIED DRUG; UNINDEXED DRUG; VERAPAMIL; 3 (2,2,2 TRIMETHYLHYDRAZINE)PROPIONATE; 3-(2,2,2-TRIMETHYLHYDRAZINE)PROPIONATE; CARDIOVASCULAR AGENT; METHYLHYDRAZINE DERIVATIVE; ORGANIC CATION TRANSPORTER; SLC22A5 PROTEIN, HUMAN;

ANIMAL CELL; ARTICLE; DRUG METABOLISM; DRUG TRANSPORT; DRUG UPTAKE; ENDOTHELIUM CELL; GENETIC TRANSFECTION; HEART; HEART ATRIUM; HUMAN; HUMAN TISSUE; IMMUNOFLUORESCENCE MICROSCOPY; IN SITU HYBRIDIZATION; LASER MICRODISSECTION; NONHUMAN; NUCLEOTIDE SEQUENCE; POLYMERASE CHAIN REACTION; PRIORITY JOURNAL; PROMOTER REGION; PROTEIN EXPRESSION; PROTEIN LOCALIZATION; PROTEIN PROTEIN INTERACTION; SINGLE NUCLEOTIDE POLYMORPHISM; AGED; ANIMAL; CELL LINE; CHEMISTRY; CYTOLOGY; DOG; FEMALE; GENETICS; GENOTYPE; HEART MUSCLE; MALE; METABOLISM; MIDDLE AGED; PHYSIOLOGY;

AGED; ANIMALS; CARDIOVASCULAR AGENTS; CELL LINE; DOGS; ENDOTHELIAL CELLS; FEMALE; GENOTYPE; HUMANS; MALE; METHYLHYDRAZINES; MIDDLE AGED; MYOCARDIUM; ORGANIC CATION TRANSPORT PROTEINS; P-GLYCOPROTEIN; POLYMERASE CHAIN REACTION; PROMOTER REGIONS (GENETICS); RNA, MESSENGER; SPIRONOLACTONE; TRANSFECTION; VERAPAMIL;

EID: 33645310407     PISSN: 00097322     EISSN: None     Source Type: Journal    
DOI: 10.1161/CIRCULATIONAHA.105.586107     Document Type: Article

References (27)

1. Koepsell H, Endou H. The SLC22 drug transporter family. Pflugers Arch. 2004;447:666-676.
2. Shitara Y, Sato H, Sugiyama Y. Evaluation of drug-drug interaction in the hepatobiliary and renal transport of drugs. Annu Rev Pharmacol Toxicol. 2005;45:689-723.
3. Wilkinson GR. Drug metabolism and variability among patients in drug response. N Engl J Med. 2005;352:2211-2221.
4. Konig J, Nies AT, Cui Y, Leier I, Keppler D. Conjugate export pumps of the multidrug resistance protein (MRP) family: localization, substrate specificity, and MRP2-mediated drug resistance. Biochim Biophys Acta. 1999;1461:377-394.
5. Haimeur A, Conseil G, Deeley RG, Cole SP. The MRP-related and BCRP/ABCG2 multidrug resistance proteins: biology, substrate specificity and regulation. Curr Drug Metab. 2004;5:21-53.
6. Thum T, Borlak J. Gene expression in distinct regions of the heart. Lancet. 2000;355:979-983.
7. Dazert P, Meissner K, Vogelgesang S, Heydrich B, Eckel L, Bohm M, Warzok R, Kerb R, Brinkmann U, Schaeffeler E, Schwab M, Cascorbi I, Jedlitschky G, Kroemer HK. Expression and localization of the multidrug resistance protein 5 (MRP5/ABCC5), a cellular export pump for cyclic nucleotides, in human heart. Am J Pathol. 2003;163:1567-1577.
8. Meissner K, Jedlitschky G, Meyer zu Schwabedissen H, Dazert P, Eckel L, Vogelgesang S, Warzok RW, Bohm M, Lehmann C, Wendt M, Cascorbi I, Kroemer HK. Modulation of multidrug resistance P-glycoprotein 1 (ABCB1) expression in human heart by hereditary polymorphisms. Pharmacogenetics. 2004;14:381-385.
9. Meissner K, Heydrich B, Jedlitschky G, Meyer zu Schwabedissen H, Mosyagin I, Dazert P, Eckel L, Vogelgesang S, Warzok RW, Böhm M, Lehmann C, Wendt M, Cascorbi I, Kroemer HK. The ATP-binding cassette transporter ABCG2 (BCRP), a marker for side population stem cells, is expressed in human heart. J Histochem Cytochem. 2006;54:215-221.
10. Tamai I, Ohashi R, Nezu J, Yabuuchi H, Oku A, Shimane M, Sai Y, Tsuji A. Molecular and functional identification of sodium ion-dependent, high affinity human carnitine transporter OCTN2. J Biol Chem. 1998;273:20378-20382.
11. Siliprandi N, Sartorelli L, Ciman M, Di Lisa F. Carnitine: metabolism and clinical chemistry. Clin Chim Acta. 1989;183:3-11.
12. Nezu J, Tamai I, Oku A, Ohashi R, Yabuuchi H, Hashimoto N, Nikaido H, Sai Y, Koizumi A, Shoji Y, Takada G, Matsuishi T, Yoshino M, Kato H, Ohura T, Tsujimoto G, Hayakawa J, Shimane M, Tsuji A. Primary systemic carnitine deficiency is caused by mutations in a gene encoding sodium ion-dependent carnitine transporter. Nat Genet. 1999;21:91-94.
13. Ganapathy ME, Huang W, Rajan DP, Carter AL, Sugawara M, Iseki K, Leibach FH, Ganapathy V. Beta-lactam antibiotics as substrates for OCTN2, an organic cation/camitine transporter. J Biol Chem. 2000;275:1699-1707.
14. Ohashi R, Tamai I, Yabuuchi H, Nezu JI, Oku A, Sai Y, Shimane M, Tsuji A. Na(+)-dependent carnitine transport by organic cation transporter (OCTN2): its pharmacological and toxicological relevance. J Pharmacol Exp Ther. 1999;291:778-784.
15. Meissner K, Sperker B, Karsten C, Zu Schwabedissen HM, Seeland U, Bohm M, Bien S, Dazert P, Kunert-Keil C, Vogelgesang S, Warzok R, Siegmund W, Cascorbi I, Wendt M, Kroemer HK. Expression and localization of P-glycoprotein in human heart: effects of cardiomyopathy. J Histochem Cytochem. 2002;50:1351-1356.
16. Peltekova VD, Wintle RF, Rubin LA, Amos CI, Huang Q, Gu X, Newman B, Van Oene M, Cescon D, Greenberg G, Griffiths AM, George-Hyslop PH, Siminovitch KA. Functional variants of OCTN cation transporter genes are associated with Crohn disease. Nat Genet. 2004;36:471-475.
17. Klein CA, Seidl S, Petat-Dutter K, Offner S, Geigl JB, Schmidt-Kittler O, Wendler N, Passlick B, Huber RM, Schlimok G, Baeuerle PA, Riethmuller G. Combined transcriptome and genome analysis of single micrometastatic cells. Nat Biotechnol. 2002;20:387-392.
18. Grube M, Schwabedissen HM, Draber K, Prager D, Moritz KU, Linnemann K, Fusch C, Jedlitschky G, Kroemer HK. Expression, localization, and function of the carnitine transporter octn2 (slc22a5) in human placenta. Drug Metab Dispos. 2005;33:31-37.
19. Schinkel AH, Wagenaar E, Van Deemter L, Mol CA, Borst P. Absence of the mdr1a P-glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A. J Clin Invest. 1995;96:1698-1705.
20. Collins-Nakai RL, Noseworthy D, Lopaschuk GD. Epinephrine increases ATP production in hearts by preferentially increasing glucose metabolism. Am J Physiol. 1994;267(5 pt 2):H1862-H1871.
21. Vaz FM, Wanders RJ. Carnitine biosynthesis in mammals. Biochem J. 2002;361(pt 3):417-429.
22. Ohashi R, Tamai I, Nezu JJ, Nikaido H, Hashimoto N, Oku A, Sai Y, Shimane M, Tsuji A. Molecular and physiological evidence for multifunctionality of carnitine/organic cation transporter OCTN2. Mol Pharmacol. 2001;59:358-366.
23. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J. The effect of spironolactone on morbidity and mortality in patients with severe heart failure: Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999;341:709-717.
24. Nedoshivin AO, Petrova NN, Kutuzova AE, Perepech NB. Effect of mildronate on life quality of patients with chronic heart failure [in Russian]. Ter Arkh. 1999;71:10-12.
25. Dambrova M, Liepinsh E, Kalvinsh I. Mildronate: cardioprotective action through carnitine-lowering effect. Trends Cardiovasc Med. 2002;12:275-279.
26. Simkhovich BZ, Shutenko ZV, Meirena DV, Khagi KB, Mezapuke RJ, Molodchina TN, Kalvins U, Lukevics E. 3-(2,2,2-Trimethylhydrazinium) propionate (THP): a novel gamma-butyrobetaine hydroxylase inhibitor with cardioprotective properties. Biochem Pharmacol. 1988;37:195-202.
27. Spaniol M, Brooks H, Auer L, Zimmermann A, Solioz M, Stieger B, Krahenbuhl S. Development and characterization of an animal model of camitine deficiency. Eur J Biochem. 2001;268:1876-1887.