Interaction of mildronate with the mitochondrial carnitine/acylcarnitine transport protein

Journal of Biochemical and Molecular Toxicology

Volumn 22, Issue 1, 2008, Pages 8-14

  Oppedisano, Francesca ^a   Fanello, Delia ^a   Calvani, Menotti ^b   Indiveri, Cesare ^a  

^a UNIVERSITY OF CALABRIA   (Italy)

^b Sigma Tau SpA   (Italy)

Author keywords

Carnitine; Mildronate; Transport

Indexed keywords

ANTIPORTER; CARNITINE; CARNITINE ACYLCARNITINE TRANSPORTER; FATTY ACID; MILDRONATE; UNCLASSIFIED DRUG;

ARTICLE; BINDING SITE; CATALYSIS; CELL TRANSPORT; COMPETITIVE INHIBITION; CYTOSOL; DRUG PROTEIN BINDING; IC 50; IN VIVO STUDY; MITOCHONDRION; PROTEOLIPOSOME;

EID: 40549118478     PISSN: 10956670     EISSN: 10990461     Source Type: Journal    
DOI: 10.1002/jbt.20208     Document Type: Article

References (30)

1. 1 Szewczyk A, Wojtczak L. Mitochondria as a pharmacological target. Pharmacol Rev 2002 ; 54: 101–127.
2. 2 Dambrova M, Liepinsh E, Kalvinsh I. Mildronate: Cardioprotective action through carnitine‐lowering effect. Trends Cardiovasc Med 2002 ; 12: 275–279.
3. 3 Simkhovich BZ, Shutenko ZV, Meirena DV, Khagi KB, Mezapuke RJ, Molodchina TN, Kalvins IJ, Lukevics E. 3‐(2,2,2‐Trimethylhydrazinium)propionate (THP)—a novel gamma‐butyrobetaine hydroxylase inhibitor with cardioprotective properties. Biochem Pharmacol 1988 ; 37: 195–202.
4. 4 Liepinsh E, Vilskersts R, Loca D, Kirjanova O, Pugovichs O, Kalvinsh I, Dambrova M. Mildronate, an inhibitor of carnitine biosynthesis, induces an increase in gamma‐butyrobetaine contents and cardioprotection in isolated rat heart infarction. J Cardiovasc Pharmacol 2006 ; 48: 314–319.
5. 5 Dhar PK, Grupp IL, Schwartz A, Grupp G, Matlib MA. Reduction of carnitine content by inhibition of its biosynthesis results in protection of isolated guinea pig hearts against hypoxic damage. J Cardiovasc Pharmacol Ther 1996 ; 1: 235–242.
6. 6 Zaugg CE, Spaniol M, Kaufmann P, Bellahcene M, Barbosa V, Tolnay M, Buser PT, Krahenbuhl S. Myocardial function and energy metabolism in carnitine‐deficient rats. Cell Mol Life Sci 2003 ; 60: 767–775.
7. 7 Spaniol M, Kaufmann P, Beier K, Wuthrich J, Torok M, Scharnagl H, Marz W, Krahenbuhl S. Mechanisms of liver steatosis in rats with systemic carnitine deficiency due to treatment with trimethylhydraziniumpropionate. J Lipid Res 2003 ; 44: 144–153.
8. 8 Spaniol M, Brooks H, Auer L, Zimmermann A, Solioz M, Stieger B, Krahenbuhl S. Development and characterization of an animal model of carnitine deficiency. Eur J Biochem 2001 ; 268: 1876–1887.
9. 9 Tsoko M, Beauseigneur F, Gresti J, Niot I, Demarquoy J, Boichot J, Bezard J, Rochette L, Clouet P. Enhancement of activities relative to fatty acid oxidation in the liver of rats depleted of L‐carnitine by D‐carnitine and a gamma‐butyrobetaine hydroxylase inhibitor. Biochem Pharmacol 1995 ; 49: 1403–1410.
10. 10 Kuwajima M, Harashima H, Hayashi M, Ise S, Sei M, Lu K, Kiwada H, Sugiyama Y, Shima K. Pharmacokinetic analysis of the cardioprotective effect of 3‐(2,2,2‐trimethylhydrazinium) propionate in mice: Inhibition of carnitine transport in kidney. J Pharmacol Exp Ther 1999 ; 289: 93–102.
11. 11 Georges B, Le Borgne F, Galland S, Isoir M, Ecosse D, Grand‐Jean F, Demarquoy J. Carnitine transport into muscular cells. Inhibition of transport and cell growth by mildronate. Biochem Pharmacol 2000 ; 59: 1357–1363.
12. 12 Grube M, Meyer zu Schwabedissen HE, Prager D, Haney J, Moritz KU, Meissner K, Rosskopf D, Eckel L, Bohm M, Jedlitschky G, Kroemer HK. Uptake of cardiovascular drugs into the human heart: Expression, regulation, and function of the carnitine transporter OCTN2 (SLC22A5). Circulation 2006 ; 113: 1114–1122.
13. 13 Sjakste N, Kleschyov AL, Boucher JL, Baumane L, Dzintare M, Meirena D, Sjakste J, Sydow K, Munzel T, Kalvinsh I. Endothelium‐ and nitric oxide‐dependent vasorelaxing activities of gamma‐butyrobetaine esters: Possible link to the antiischemic activities of mildronate. Eur J Pharmacol 2004 ; 495: 67–73.
14. 14 Sjakste N, Baumane L, Boucher JL, Dzintare M, Meirena D, Sjakste J, Lauberte L, Kalvinsh I. Effects of gamma‐butyrobetaine and mildronate on nitric oxide production in lipopolysaccharide‐treated rats. Basic Clin Pharmacol Toxicol 2004 ; 94: 46–50.
15. 15 Degrace P, Demizieux L, Gresti J, Tsoko M, Andre A, Demaison L, Clouet P. Fatty acid oxidation and related gene expression in heart depleted of carnitine by mildronate treatment in the rat. Mol Cell Biochem 2004 ; 258: 171–182.
16. 16 Peschechera A, Scalibastri M, Russo F, Giarrizzo MG, Carminati P, Giannessi F, Arduini A, Ricciolini R. Carnitine depletion in rat pups from mothers given mildronate: A model of carnitine deficiency in late fetal and neonatal life. Life Sci 2005 ; 77: 3078–3091.
17. 17 Indiveri C, Tonazzi A, Palmieri F. Identification and purification of the carnitine carrier from rat liver mitochondria. Biochim Biophys Acta 1990 ; 1020: 81–86.
18. 18 Palmieri F, Indiveri C, Bisaccia F, Kramer R. Functional properties of purified and reconstituted mitochondrial metabolite carriers. J Bioenerg Biomembr 1993 ; 25: 525–535.
19. 19 Indiveri C, Tonazzi A, Palmieri F. The reconstituted carnitine carrier from rat liver mitochondria: Evidence for a transport mechanism different from that of the other mitochondrial translocators. Biochim Biophys Acta 1994 ; 1189: 65–73.
20. 20 Indiveri C, Tonazzi A, Giangregorio N, Palmieri F. Probing the active site of the reconstituted carnitine carrier from rat liver mitochondria with sulfhydryl reagents. A cysteine residue is localized in or near the substrate binding site. Eur J Biochem 1995 ; 228: 271–278.
21. 21 Indiveri C, Iacobazzi V, Giangregorio N, Palmieri F. The mitochondrial carnitine carrier protein: cDNA cloning, primary structure and comparison with other mitochondrial transport proteins. Biochem J 1997 ; 321: 713–719.
22. 22 Kramer R, Heberger C. Functional reconstitution of carrier proteins by removal of detergent with ahydrophobic ion exchange column. Biochim Biophys Acta 1986 ; 863: 289–296.
23. 23 Palmieri F, Indiveri C, Bisaccia F, Iacobazzi V. Mitochondrial metabolite carrier proteins: Purification, reconstitution, and transport studies. Methods Enzymol 1995 ; 260: 349–369.
24. 24 Palmieri F, Klingenberg M. Direct methods for measuring metabolite transport and distribution in mitochondria. Methods Enzymol 1979 ; 56: 279–301.
25. 25 Dulley JR, Grieve PA. A simple technique for eliminating interference by detergents in the Lowry method of protein determination. Anal Biochem 1975 ; 64: 136–141.
26. 26 Dixon M. The determination of enzyme inhibitor constants. Biochem J 1953 ; 55: 170–171.
27. 27 Tonazzi A, Giangregorio N, Palmieri F, Indiveri C. Relationships of cysteine and lysine residues with the substrate binding site of the mitochondrial ornithine/citrulline carrier: An inhibition kinetic approach combined with the analysis of the homology structural model. Biochim Biophys Acta 2005 ; 1718: 53–60.
28. 28 Eaton S. Control of mitochondrial beta‐oxidation flux. Prog Lipid Res 2002 ; 41: 197–239.
29. 29 Pochini L, Oppedisano F, Indiveri C. Reconstitution into liposomes and functional characterization of the carnitine transporter from renal cell plasma membrane. Biochim Biophys Acta 2004 ; 1661: 78–86.
30. 30 Ohashi R, Tamai I, Nezu JI, 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.