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Carnitine
Systematic (IUPAC) name
3-Hydroxy-4-trimethylammonio-butanoate
Identifiers
CAS number 541-15-1
ATC code A16AA01
PubChem 288
DrugBank APRD01070
ChemSpider 282
Chemical data
Formula C 7H15NO3  
Mol. mass 161.199 g/mol
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability < 10%
Protein binding None
Metabolism slightly
Half life  ?
Excretion Urine (> 95%)
Therapeutic considerations
Pregnancy cat.  ?
Legal status
Routes oral and iv
 Yes check.svgY(what is this?)  (verify)

Carnitine is a quaternary ammonium compound biosynthesized from the amino acids lysine and methionine.[1] In living cells, it is required for the transport of fatty acids from the cytosol into the mitochondria during the breakdown of lipids (or fats) for the generation of metabolic energy. It is often sold as a nutritional supplement. Carnitine was originally found as a growth factor for mealworms and labeled vitamin Bt. Carnitine exists in two stereoisomers: its biologically active form is L-carnitine, while its enantiomer, D-carnitine, is biologically inactive.[2]

Contents

Biochemistry

Production

In animals, carnitine is biosynthesized primarily in the liver and kidneys from the amino acids lysine or methionine.[3] Vitamin C (ascorbic acid) is essential to the synthesis of carnitine. During growth[4] or pregnancy[5] the requirement of carnitine might exceed its natural production.

Role in fatty acid metabolism

Carnitine transports long-chain acyl groups from fatty acids into the mitochondrial matrix, so that they can be broken down through β-oxidation to acetate to obtain usable energy via the citric acid cycle. In some organisms such as fungi, the acetate is used in the glyoxylate cycle for gluconeogenesis and formation of carbohydrates. Fatty acids must be activated before binding to the carnitine molecule to form acyl-carnitine. The free fatty acid in the cytosol is attached with a thioester bond to coenzyme A (CoA). This reaction is catalyzed by the enzyme fatty acyl-CoA synthetase and driven to completion by inorganic pyrophosphatase.

The acyl group on CoA can now be transferred to carnitine and the resulting acyl-carnitine transported into the mitochondrial matrix. This occurs via a series of similar steps:

  1. Acyl-CoA is conjugated to carnitine by carnitine acyltransferase I (palmitoyltransferase) located on the outer mitochondrial membrane
  2. Acyl-carnitine is shuttled inside by a carnitine-acylcarnitine translocase
  3. Acyl-carnitine is converted to acyl-CoA by carnitine acyltransferase II (palmitoyltransferase) located on the inner mitochondrial membrane. The liberated carnitine returns to the cytosol.

Human genetic disorders such as primary carnitine deficiency, carnitine palmitoyltransferase I deficiency, carnitine palmitoyltransferase II deficiency and carnitine-acylcarnitine translocase deficiency affect different steps of this process.[6]

Carnitine acyltransferase I undergoes allosteric inhibition as a result of malonyl-CoA, an intermediate in fatty acid biosynthesis, in order to prevent futile cycling between β-oxidation and fatty acid synthesis.

Click to enlarge

Physiological effects

Effects on bone mass

In the course of human aging, carnitine concentration in cells diminishes, affecting fatty acid metabolism in various tissues. Particularly adversely affected are bones which require continuous reconstructive and metabolic functions of osteoblasts for maintenance of bone mass.

There is a close correlation between changes in plasma levels of osteocalcin and osteoblast activity and a reduction in osteocalcin plasma levels is an indicator of reduced osteoblast activity,[7] which appears to underlie osteoporosis in elderly subjects and in postmenopausal women. Administration of a carnitine mixture or propionyl-L-carnitine is capable of increasing serum osteocalcin concentrations of animals thus treated, whereas serum osteocalcin levels tend to decrease with age in control animals.[8]

Antioxidant effects

The carnitines exert a substantial antioxidant action, thereby providing a protective effect against lipid peroxidation of phospholipid membranes and against oxidative stress induced at the myocardial and endothelial cell level.[9]

Potential uses as a pharmaceutical

Heart Conditions

Carnitine is primarily used for heart-related conditions. Several clinical trials show that L-carnitine and propionyl-L-carnitine can be used along with conventional treatment for angina to reduce medication needs and improve the ability of those with angina to exercise without chest pain. [10] [11] There is little evidence about a positive effect of the use of carnitine after a heart attack. Some small researches suggest that people taking L-carnitine may be less likely to suffer a subsequent heart attack or experience chest pain and abnormal heart rhythms. [12] However, other studies show there’s no obvious benefit. [13]

Effects on diabetes

L-Carnitine improved glucose disposal among 15 patients with type II diabetes and 20 healthy volunteers.[14] Glucose storage increased between both groups, but glucose oxidation increased only in the diabetic group. Finally, glucose uptake increased about 8% for both.

Kidney Disease and Dialysis

Due to the fact that kidneys produce carnitine, kidney disease may lead to the deficiency of carnitine in the body. Thus, carnitine may be prescribed to those with kidney disease. [15]

Effect in male infertility

The use of carnitine showed some promise in a controlled trial in selected cases of male infertility improving sperm quality.[16]

As a weight loss supplement

"Although L-carnitine has been marketed as a weight-loss supplement, there is no scientific evidence to date to show that it improves weight loss. " [17]

Regular supplements of L-carnitine, however, contribute to energy metabolism and improved neurotransmitter function in the brain in elderly.[18]

As an antidote in valproic acid poisoning

"[In the treatment of valproate toxicity] L-carnitine supplementation ...is thought to provide benefit, particularly in patients with concomitant hyperammonemia, encephalopathy, and/or hepatotoxicity."[19] Further trials are warranted, as benefit is largely theoretical, rather than proven at this stage.

Sources

Food

The highest concentrations of carnitine are found in red meat and dairy products. Other natural sources of carnitine include nuts and seeds (e.g., pumpkin, sunflower, sesame), legumes or pulses (beans, peas, lentils, peanuts), vegetables (artichokes, asparagus, beet greens, broccoli, brussels sprouts, collard greens, garlic, mustard greens, okra, parsley, kale), fruits (apricots, bananas), cereals (buckwheat, corn, millet, oatmeal, rice bran, rye, whole wheat, wheat bran, wheat germ) and other "health" foods (bee pollen, brewer's yeast, carob).

Product Quantity Carnitine
Beef steak 100 g 95 mg
Ground beef 100 g 94 mg
Pork 100 g 27.7 mg
Bacon 100 g 23.3 mg
Tempeh 100 g 19.5 mg
Cod fish 100 g  5.6 mg
Chicken breast 100 g  3.9 mg
American cheese 100 g  3.7 mg
Ice cream 100 ml  3.7 mg
Whole milk 100 ml  3.3 mg
Avocado one medium 2 mg[20]
Cottage cheese 100 g  1.1 mg
Whole-wheat bread 100 g  0.36 mg
Asparagus 100 g  0.195 mg
White bread 100 g  0.147 mg
Macaroni 100 g  0.126 mg
Peanut butter 100 g  0.083 mg
Rice (cooked) 100 g  0.0449 mg
Eggs 100 g  0.0121 mg
Orange juice 100 ml  0.0019 mg

Generally, 20 to 200 mg are ingested per day by those on an omnivorous diet, while those on a strict vegetarian or vegan diet may ingest as little as 1 mg/day. No advantage appears to exist in giving an oral dose greater than 2 g at one time, since absorption studies indicate saturation at this dose.[21]

Other sources

Other sources may be found in over-the-counter vitamins, energy drinks and various other products. Products containing L-carnitine cannot be marketed as "natural health products" in Canada. L-Carnitine products and supplements are not allowed to be imported into Canada (Health Canada).[22]

See also

References

  1. ^ Steiber A, Kerner J, Hoppel C (2004). "Carnitine: a nutritional, biosynthetic, and functional perspective". Mol. Aspects Med. 25 (5-6): 455–73. doi:10.1016/j.mam.2004.06.006. PMID 15363636.  
  2. ^ A. J. Liedtke, S. H. Nellis, L. F. Whitesell and C. Q. Mahar (1 November 1982). "Metabolic and mechanical effects using L- and D-carnitine in working swine hearts". Heart and Circulatory Physiology 243 (5): H691–H697. PMID 7137362. http://ajpheart.physiology.org/cgi/content/abstract/243/5/H691.  
  3. ^ "L-Carnitine". http://www.pdrhealth.com/drug_info/nmdrugprofiles/nutsupdrugs/lca_0060.shtml. Retrieved 2007-06-01.  
  4. ^ Cederblad, G; Niklasson, A; Rydgren, B; Albertsson-Wikland, K; Olegård, R; “Carnitine in Maternal and Neonatal Plasma”; Acta Pædiatrica; Published Online: 21 Jan 2008; Volume 74, Issue 4: Pp 500 – 504
  5. ^ Cederblad, G; Fahraeus, L; Lindgren, K; “Plasma carnitine and renal-carnitine clearance during pregnancy”; American Journal of Clinical Nutrition; 1986; Volume 44:Pp
  6. ^ Olpin S (2005). "Fatty acid oxidation defects as a cause of neuromyopathic disease in infants and adults". Clin. Lab. 51 (5-6): 289–306. PMID 15991803.  
  7. ^ Claudio Cavazza, Composition for the Prevention and Treatment of Osteoporosis due to Menopause Syndrome (2002), US Patent 6,335,038, column 4.
  8. ^ Claudio Cavazza, Composition for the Prevention and Treatment of Osteoporosis due to Menopause Syndrome (2002), US Patent 6,335,038, columns 3-4.
  9. ^ Claudio Cavazza, Composition for the Prevention and Treatment of Osteoporosis due to Menopause Syndrome (2002), US Patent 6,335,038, column 3.
  10. ^ Cacciatore L, Cerio R, Ciarimboli M, Cocozza M, Coto V, D'Alessandro A, D'Alessandro L, Grattarola G, Imparato L, Lingetti M (1991). "The therapeutic effect of L-carnitine in patients with exercise-induced stable angina: a controlled study.". Drugs Exp Clin Res 17 (4): 225-235. PMID 1794297.  
  11. ^ Bartels GL, Remme WJ, Pillay M, et al. (July 1994). "Effects of L-propionylcarnitine on ischemia-induced myocardial dysfunction in men with angina pectoris". The American Journal of Cardiology 74 (2): 125-130. doi:10.1016/0002-9149(94)90084-1.  
  12. ^ Michael A. Arsenian (November - December 1997). "Carnitine and its derivatives in cardiovascular disease". Progress in Cardiovascular Diseases 40 (3): 265-286. doi:10.1016/S0033-0620(97)80037-0.  
  13. ^ Kamyar Kalantar-Zadeh, MPHa, Stefan D. Anker, Tamara B. Horwich and Gregg C. Fonarow (June 2008). "Nutritional and Anti-Inflammatory Interventions in Chronic Heart Failure". The American Journal of Cardiology 101 (11): S89-S103. doi:10.1016/j.amjcard.2008.03.007.  
  14. ^ Geltrude Mingrone, Aldo V. Greco, Esmeralda Capristo, Giuseppe Benedetti, Annalisa Giancaterini, Andrea De Gaetano, and Giovanni Gasbarrini (1 February 1999). "L-Carnitine Improves Glucose Disposal in Type 2 Diabetic Patients". Journal of the American College of Nutrition 18 (1): 77–82. PMID 10067662. http://www.jacn.org/cgi/content/full/18/1/77.  
  15. ^ Wei Huang, Sobia N. Shaikh, Malliga E. Ganapathy, Ullrich Hopfer, Frederick H. Leibach, A. Lee Carter and Vadivel Ganapathy (October 1999). "Carnitine transport and its inhibition by sulfonylureas in human kidney proximal tubular epithelial cells". Biochemical Pharmacology 58 (8): 1361-1370. doi:10.1016/S0006-2952(99)00219-1.  
  16. ^ Lenzi A, Lombardo F, Sgro P, Salacone P, Caponecchia L, Dondero F, Gandini L (2003). "Use of carnitine therapy in selected cases of male factor infertility: a double-blind crossover trial.". Fertility and Sterility (2003), Volume 79 , Issue 2 , Pages 292 - 300 79 (2): 292–300. PMID 12568837.  
  17. ^ "University of Maryland Medical Centre, April 2002". http://www.umm.edu/altmed/articles/carnitine-l-000291.htm. Retrieved 2008-05-20.  
  18. ^ Mariano Malaguarnera, Lisa Cammalleri, Maria Pia Gargante, Marco Vacante, Valentina Colonna and Massimo Motta: "L-Carnitine treatment reduces severity of physical and mental fatigue and increases cognitive functions in centenarians: a randomized and controlled clinical trial", American Journal of Clinical Nutrition, Vol. 86, No. 6, 1738-1744, December 2007
  19. ^ "Toxicity, Valproate: Treatment & Medication". http://emedicine.medscape.com/article/819315-treatment.  
  20. ^ Linus Pauling Institute at Oregon State University
  21. ^ http://www.encyclopedia.com/doc/1G1-131086133.html
  22. ^ "NHPD Monthly Communique, Vol. 1, Issue 1, September 2005". http://www.hc-sc.gc.ca/dhp-mps/prodnatur/bulletins/_communiques/communique_sep05-eng.php. Retrieved 2007-06-01.  

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