Journal of Renal Nutrition
Volume 13, Issue 1 , Pages 2-14 , January 2003

History of L-carnitine: Implications for renal disease

  • Mario Matera, MD

      Affiliations

    • Department of Pharmacology 2nd, and the Department of Experimental and Clinical Pharmacology, Medical Faculty, University of Catania, Catania
  • ,
  • Guido Bellinghieri, MD

      Affiliations

    • Department of Nephrology, University of Messina, Messina, Italy
  • ,
  • Giuseppe Costantino, MD

      Affiliations

    • Department of Pharmacology 2nd, and the Department of Experimental and Clinical Pharmacology, Medical Faculty, University of Catania, Catania
  • ,
  • Domenico Santoro, MD

      Affiliations

    • Department of Nephrology, University of Messina, Messina, Italy
  • ,
  • Menotti Calvani, MD

      Affiliations

    • Department of Nephrology, University of Messina, Messina, Italy
  • ,
  • Vincenzo Savica, MD

      Affiliations

    • Department of Nephrology, University of Messina, Messina, Italy

References 

  1. Glulewitsch WI, Krimberg R. Carnitine. In: 10th ed. Goodmann , Gilmann  editor. The Pharmacological Basis of Therapeutics. New York: McGraw-Hill; 2001;p. 1766–1767
  2. Ito T, Fraenkel G. The effect of nitrogen starvation on tenebrio molitor. J Insect Physiol. 1966;12:803–817
  3. Fritz IB, Marquis NR. The role of acylcarnitine esters and carnitine palmityltransferase in the transport of fatty acyl groups across mitochondrial membranes. Proc Natl Acad Sci U S A. 1965;54:1226–1233
  4. Editorial Carnitina deficiency. Lancet 1990. 1990;335:631–633
  5. Bremer J. Carnitine-metabolism and functions. Physiol Rev. 1983;63:1420–1480
  6. Pande SV, Parvin R. Characterization of carnitine acylcarnitine translocase system of heart mitochondria. J Biol Chem Nov. 1976;251:6683–6691
  7. Saheki T. Carnitine as a vitamin-like biofactor. Nippon Rinsho. 1999;57:2270–2275
  8. Rebouch CJ, Paulson DJ. Carnitine metabolism and function in humans. Ann Rev Nutr. 1986;6:41–66
  9. Rebouche CJ. Carnitine function and requirements during the life cycle. FASEB J. 1992;6:3379–3386
  10. Bieber LL. Carnitine. Ann Rev Biochem. 1988;57:261–283
  11. Zeyner A, Harmeyer J. Metabolic functions of L-carnitine and its effects as feed additive in horses. A review. Arch Tierernahr. 1999;52:115–138
  12. Wu X, Huang W, Prasad PD, Seth P, et al.  Functional characteristics and tissue distribution pattern of organic cation transporter 2 (OCTN2), an organic cation/carnitine transporter. J Pharmacol Exp Ther. 1999;290:1482–1492
  13. Ohashi R, Tamai I, Yabuuchi H, et al.  Na(+)-dependent carnitine transport by organic cation transporter (OCTN2): Its pharmacological and toxicological relevance. J Pharmacol Exp Ther. 1999;291:778–784
  14. Szilagyi M. L-carnitine as essential methylated compound in animal metabolism. An overview. Acta Biol Hung. 1998;49:209–218
  15. Fritz IB, Burdzy K. Novel action of carnitine: Inhibition of aggregation of dispersed cells elicited by clusterin in vitro. J Cell Physiol. 1989;140:18–28
  16. Boots MR, Wolfe ML, Boots SG, et al.  Effect of carnitine analogs on carnitine acetyltransferase. J Pharm Sci Feb. 1980;69:202–204
  17. Paulson DJ, Shug AL. Inhibition of the adenine nucleotide translocator by matrix-localized palmityl-CoA in rat heart mitochondria. Biochim Biophys Acta. 1984;766:70–76
  18. Lahjouji K, Mitchell GA, Qureshi IA. Carnitine transport by organic cation transporters and systemic carnitine deficiency. Mol Genet Metab. 2001;73:287–297
  19. Roodyn DB. Mitochondrial biogenesis: Germ free mitochondria. FEBS Lett. 1968;1:203–205
  20. Hartman H, Fedorov A. The origin of the eucariotic cell. Proc Natl Acad Sci USA. 2002;99:1420–1425
  21. Acuna CD, Escames G, Carazo A, et al.  Melatonin, mitochondrial homeostasis and mitochondrial-related diseases. Curr Top Med Chem. 2002;2:133–151
  22. Dellinger M, Geze M. Detection of mitochondrial DNA in living animal cells with fluorescence. J Microsc. 2001;204:196–202
  23. Miura K, Aminova L, Murayama Y. Fusarenon X induced apoptosis in HL-60 cells depends on caspase activation and cytochrome c release. Toxicology. 2002;172:103–112
  24. Santore M, McClintock DS, Lee VY, et al.  Anoxia-induced apoptosis occurs through a mitochondria-dependent pathway in lung epithelial cells. Am J Physiol Lung Cell Mol Physiol. 2002;282:L727–L734
  25. Bhat HK. Depletion of mitochondrial DNA and enzyme in estrogen-induced hamster kidney tumors: A rodent model of hormonal carcinogenesis. J Biochem Mol Toxicol. 2002;16:1–9
  26. Bornstein B, Mas JA, Fernandez-Moreno MA, et al.  The A8296G mtDNA mutation associated with several mitochondrial diseases does not cause mitochondrial dysfunction in cybrid cell lines. Hum Mutat. 2002;19:234–239
  27. Ramsay RR. The carnitine acyltransferases: Modulators of acyl-CoA-dependent reactions. Biochem Soc Trans. 2000;28:182–186
  28. Pande SV. A mitochondrial carnitine acylcarnitine translocase system. Proc Natl Acad Sci U S A. 1975;72:883–887
  29. Ramsay RR, Gandour RD, van der Leij FR. Molecular enzymology of carnitine transfer and transport. Biochim Biophys Acta. 2001;1546:21–43
  30. Pande SV, Parvin R. Characterization of carnitine acylcarnitine translocase system of heart mitochondria. J Biol Chem. 1976;251:6683–6691
  31. Idell-Wenger JA. Carnitine: Acylcarnitine translocase of rat heart mitochondria. Competition for carnitine uptake by carnitine esters. J Biol Chem. 1981;256:5597–5603
  32. Parvin R, Pande SV. Enhancement of mitochondrial carnitine and carnitine acylcarnitine translocase-mediated transport of fatty acids into liver mitochondria under ketogenic conditions. J Biol Chem. 1979;254:5423–5429
  33. Pande SV, Parvin R. Carnitine-acylcarnitine translocase catalyzes an equilibrating unidirectional transport as well. J Biol Chem. 1980;255:2994–3001
  34. Bieber LL. Carnitine. Ann Rev Biochem. 1988;57:261–283
  35. Edwards YH, Chase JF, Edwards MR, et al.  Carnitine acetyltransferase: The question of multiple forms. Eur J Biochem. 1974;46:209–215
  36. Miyazawa S, Ozasa H, Furuta S, et al.  Biosynthesis and turnover of carnitine acetyltransferase in rat liver. J Biochem (Tokyo). 1983;93:259–453
  37. Miyazawa S, Ozasa H, Furuta S, et al.  Purification and properties of carnitine acetyltransferase from rat liver. J Biochem (Tokyo). 1983;93:439–451
  38. Ueda M, Robinson FW, Smith MM, et al.  Effects of divalent cations on the regulation of insulin-sensitive glucose transport and cAMP phosphodiesterase in adipocytes. Insulin-like effects of divalent cations. J Biol Chem. 1984;259:9520–9525
  39. Farrell SO, Fiol CJ, Reddy JK, et al.  Properties of purified carnitine acyltransferases of mouse liver peroxisomes. J Biol Chem. 1984;259:13089–13095
  40. Bieber LL, Krahling JB, Clarke PR, et al.  Carnitine acyltransferases in rat liver peroxisomes. Arch Biochem Biophys. 1981;211:599–604
  41. Miyazawa S, Ozasa H, Osumi T, et al.  Purification and properties of carnitine octanoyltransferase and carnitine palmitoyltransferase from rat liver. J Biochem (Tokyo). 1983;94:529–542
  42. Derrick JP, Ramsay RR. L-carnitine acyltransferase in intact peroxisomes is inhibited by malonyl-CoA. Biochem J. 1989;262:801–806
  43. Lysiak W, Lilly K, DiLisa F, et al.  Quantitation of the effect of L-carnitine on the levels of acid-soluble short-chain acyl-CoA and CoASH in rat heart and liver mitochondria. J Biol Chem. 1988;263:1151–1156
  44. Brady PS, Ramsay RR, Brady LJ. Regulation of the long-chain carnitine acyltransferases. FASEB J. 1993;7:1039–1044
  45. Koizumi A, Nozaki J, Ohura T, et al.  Genetic epidemiology of the carnitine transporter OCTN2 gene in a Japanese population and phenotypic characterization in Japanese pedigrees with primary systemic carnitine deficiency. Hum Mol Genet. 1999;8:2247–2254
  46. Huang W, Shaikh SN, Ganapathy ME, et al.  Carnitine transport and its inhibition by sulfonylureas in human kidney proximal tubular epithelial cells. Biochem Pharmacol. 1999;58:1361–1370
  47. Zeyner A, Harmeyer J. Metabolic functions of L-carnitine and its effects as feed additive in horses. A review. Arch Tierernahr. 1999;52:115–138
  48. Colquhoun A. Induction of apoptosis by polyunsaturated fatty acids and its relationship to fatty acid inhibition of carnitine palmitoyltransferase I activity in Hep2 cells. Biochem Mol Biol Int. 1998;45:331–336
  49. Ashakumary L, Rouyer I, Takahashi Y, et al.  Sesamin, a sesame lignan, is a potent inducer of hepatic fatty acid oxidation in the rat. Metabolism. 1999;48:1303–1313
  50. Rebouche CJ. Renal handling of carnitine in experimental vitamin C deficiency. Metabolism. 1995;44:1639–1643
  51. Savica V, Bellinghieri G, Lamanna F. The hypotriglyceridemic action of the combination of L-carnitine + simvastatin vs. L-carnitine and vs. simvastatin. Clin Ter. 1992;140:17–22
  52. Goa KL, Brogden RN:, L-Carnitine . A preliminary review of its pharmacokinetics, and its therapeutic use in ischaemic cardiac disease and primary and secondary carnitine deficiencies in relationship to its role in fatty acid metabolism. Drugs. 1987;34:1–24
  53. Rebouche CJ, Seim H. Carnitine metabolism and its regulation in microorganisms and mammals. Ann Rev Nutr. 1998;18:39–61
  54. Rebouche CJ. Ascorbic acid and carnitine biosynthesis. Am J Clin Nutr. 1991;54:1147S–1152S
  55. Rebouche CJ, Bosch EP, Chenard CA, et al.  Utilization of dietary precursors for carnitine synthesis in human adults. J Nutr. 1989;119:1907–1913
  56. Spaniol M, Brooks H, Auer L, et al.  Development and characterization of an animal model of carnitine deficiency. Eur J Biochem. 2001;268:1876–1887
  57. Cornelio F, Di Donato S. Myopathies due to enzyme deficiencies. J Neurol. 1985;232:329–340
  58. Scholte HR, de Jonge PC. Carnitine deficit. In:  Giltzelman R,  Baerlocker K,  Steinemann B editor. Carnitne in der Medizine. Stuttgart: Shattauer; 1987;p. 22–59
  59. Vaz FM, Scholte HR, Ruiter J, et al.  Identification of two novel mutations in OCTN2 of three patients with systemic carnitine deficiency. Hum Genet. 1999;105:157–161
  60. van der Leij FR, Drijfholt A, Kuipers JR. Rationale for a conditional knockout mouse model to study carnitine palmitoyltransferase I deficiencies. Adv Exp Med Biol. 1999;466:377–385
  61. Treem WR, Stanley CA, Finegold DN, et al.  Primary carnitine deficiency due to a failure of carnitine transport in kidney, muscle, and fibroblasts. N Engl J Med. 1988;319:1331–1336
  62. Lahjouji K, Malo C, Mitchell GA, et al.  L-carnitine transport in mouse renal and intestinal brush-border and basolateral membrane vesicles. Biochim Biophys Acta. 2002;1558:82–93
  63. Pande SV. Uneven distribution of palmitoyl carnitine in solutions because of migration to air/water interphase. Biochim Biophys Acta. 1981;663:669–673
  64. McGarry JD, Mannaerts GP, Foster DW. A possible role for malonyl-CoA in the regulation of hepatic fatty acid oxidation and keratogenesis. J Clin Invest. 1977;60:265–270
  65. Evans AM, Faull R, Fornasini G, et al.  Pharmacokinetics of L-carnitine in patients with end-stage renal disease undergoing long-term haemodialysis. Clin Pharmacol Ther. 2000;68:238–249
  66. Shaw RD, Li BUK, Hamilton JW, et al.  Carnitine transport in rat small intestine. Am J Physiol. 1983;245:376–381
  67. Wanner C, Förster-Wanner S, Rössle C, et al.  Carnitine metabolism in patients with chronic renal failure: Effect of L-carnitine supplementation. Kidney Int. 1987;32(suppl 22):132S–135S
  68. Ohashi R, Tamai I, Yabuuchi H, et al.  Na(+)-dependent carnitine transport by organic cation transporter (OCTN2): Its pharmacological and toxicological relevance. J Pharmacol Exp Ther. 1999;291:778–784
  69. Zhu Y, Jong MC, Frazer KA, et al.  Genomic interval engineering of mice identifies a novel modulator of triglycerides production. Proc Natl Acad Sci USA. 2000;97:1137–1142
  70. Lennon DL, Shrago E, Madden M, et al.  Carnitine status, plasma lipid profiles, and exercise capacity of dialysis patients: effects of a submaximal exercise program. Metabolism. 1986;35:728–735
  71. De los Reyes B, Navarro JA, Perez-Garcia R, et al.  Effects of L-carnitine on erythrocyte acyl-CoA, free CoA, and glycerophospholipid acyltransferase in uremia. Am J Clin Nutr. 1998;67:386–390
  72. Spagnoli LG, Palmieri G, Mauriello A, et al.  Morphometric evidence of the trophic effect of L-carnitine on human skeletal muscle. Nephron. 1990;55:16–23
  73. Guarnieri G, Situlin R, Biolo G. Carnitine metabolism in uremia. Am J Kidney Dis. 2001;38(suppl 4):S63–S67
  74. Bellinghieri G, Savica V, Mallamace A, et al.  Correlation between increased serum and tissue L-carnitine levels and improved muscle symptoms in hemodialysis patients. Am J Clin Nutr. 1983;38:523–531
  75. Brass EP, Adler S, Sietsema KE, et al.  Intravenous L-carnitine increases plasma carnitine, reduces fatigue, and may preserve exercise capacity in hemodialysis. Am J Kidney Dis. 2001;37:1018–1028
  76. Debska-Slizien , Kawecka A, Wojanarowsky K, et al.  Correlation between plasma carnitine, muscle carnitine and glycogen levels in maintenance hemodialysis patients. Int J Artif Organs. 2000;23:90–96
  77. Matsumoto Y, Sato M, Ohashi H, et al.  Effects of L-carnitine supplementation on cardiac morbidity in haemodialysis patients. Am J Nephrol. 2001;20:201–207
  78. Hurot JM, Cucherat M, Haugh M, et al.  Effects of L-carnitine supplementation in maintenance hemodialysis patients: A systematic review. J Am Soc Nephrol. 2002;13:708–714
  79. Matsumoto Y, Amano I, Hirose S, et al.  Effects of L-carnitine supplementation on renal anemia in poor responders to erythropoietin. Blood Purif. 2001;19:24–32
  80. Labonia WD, Morelli OH, Gimenez MI, et al.  Effects of levo-carnitine on sodium transport in erythrocytes from dialysed uremic patients. Kidney Int. 1987;32:754–759
  81. Matsumura M, Hatakeyama S, Koni I, et al.  Correlation between serum carnitine levels and erythrocyte osmotic fragility in haemodialysis patients. Nephron. 1996;72:574–578
  82. Nikolaos S, George A, Telemachos T, et al.  Effect of L-carnitine supplementation red blood cells deformability in hemodialysis patients. Ren Failure. 2000;22:73–80
  83. Wanic-Kossowska Mpiszczek I, Rogacka D, Czarnecki R, et al.  The efficacy of the substitution of carnivit in patients with chronic failure treated with hemodialysis. Pol Arch Med Wewn. 1999;102:885–891
  84. Sakurabayashi T, Takaesu Y, Haginoshita S, et al.  Improvement of myocardial fatty acid metabolism through L-carnitine administration to chronic hemodialysis patients. Am J Nephrol. 1999;19:480–484

 Address reprint requests to Domenico Santoro, MD, C.da Conte Coop. Sperone is.3 pal. E, 98-168 Messina, Italy.

PII: S1051-2276(02)13411-X

doi: 10.1053/jren.2003.50010

Journal of Renal Nutrition
Volume 13, Issue 1 , Pages 2-14 , January 2003