Carnitine

Carnitine

Systematic (IUPAC) name
3-hydroxy-4-(trimethylazaniumyl)butanoate
Clinical data
AHFS/Drugs.com	Micromedex Detailed Consumer Information
Pregnancy cat.	?
Legal status	?
Routes	oral and iv
Pharmacokinetic data
Bioavailability	< 10%
Protein binding	None
Metabolism	slightly
Excretion	Urine (> 95%)
Identifiers
CAS number	541-15-1 Y
ATC code	A16AA01
PubChem	CID 288
DrugBank	APRD01070
ChemSpider	282 Y
UNII	0G389FZZ9M Y
KEGG	C00318 Y
ChEBI	CHEBI:17126 Y
ChEMBL	CHEMBL172513 Y
Chemical data
Formula	C7H15NO3
Mol. mass	161.199 g/mol
SMILES	eMolecules & PubChem
InChI InChI=1S/C7H15NO3/c1-8(2,3)5-6(9)4-7(10)11/h6,9H,4-5H2,1-3H3 Y Key:PHIQHXFUZVPYII-UHFFFAOYSA-N Y
N(what is this?)  (verify)

Carnitine should not be confused with Carnosine.

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 (fats) for the generation of metabolic energy. It is widely available 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, whereas its enantiomer, D-carnitine, is biologically inactive.^[2]

Biochemistry

Biosynthesis

In animals, carnitine is biosynthesized primarily in the liver and kidneys from the amino acids lysine (via trimethyllysine) 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 they can be broken down through β-oxidation to Acetyl CoA 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 acylcarnitine. 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 acylcarnitine 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. Acylcarnitine is shuttled inside by a carnitine-acylcarnitine translocase
3. Acylcarnitine 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, to prevent futile cycling between β-oxidation and fatty acid synthesis.

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 studies 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 have not found similar benefits.^[13] Further research on this subject is needed.

Kidney disease and dialysis

Because 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.^[14]

Effect in male infertility

The use of carnitine showed some promise in a controlled trial in selected cases of male infertility by improving sperm quality.^[15] L-carnitine supplementation has also shown to have beneficial effects in the treatment of varicocele, a major cause of male infertility. ^[16]

As a weight loss supplement

"Although L-carnitine has been marketed as a weight-loss supplement, there is no scientific evidence to show that it improves weight loss; however, some studies show that oral carnitine reduces fat mass, increases muscle mass, and reduces fatigue. All of these effects may contribute to weight loss."^[17] Furthermore, whereas researchers in the 20th century failed to show that muscle carnitine content could be increased by dietary supplementation, this may have been in part due to inadequate lengths of the supplementation periods.^[18] In 2011, researchers using L-carnitine L-tartrate supplementation for 6 months in a well controlled study demonstrated not only increased muscle carnitine in subjects without carnitine deficiencies, but also an impact on muscle metabolism and performance; however, measurements of lipid oxidation were not taken in this study, and further research is needed.^[19]

Regular supplements of L-carnitine, however, contribute to energy metabolism and improved neurotransmitter function in the brain in elderly patients.^[20]

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."^[21] 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).^{[citation needed]}

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[22]
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

In general, 20 to 200 mg are ingested per day by those on an omnivorous diet, whereas those on a strict vegetarian or vegan diet may ingest as little as 1 mg/day.^[23] 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.^[24]

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).^[25]

See also

• Acetylcarnitine
• Primary carnitine deficiency

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". Archived from the original on 2007-05-08. http://web.archive.org/web/20070508224849/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. PMID 8023775. 
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. PMID 9406679. 
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. PMID 18514634. 
14. ^ 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. PMID 10487540. 
15. ^ 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. 
16. ^ Seo JT, Kim KT, Moon MH, Kim WT (April 2010). "The significance of microsurgical varicocelectomy in the treatment of subclinical varicocele". Fertil. Steril. 93 (6): 1907–10. doi:10.1016/j.fertnstert.2008.12.118. PMID 19249033. 
17. ^ University of Maryland Medical Center
18. ^ Sahlin K (2010). "Boosting fat burning with carnitine: an old friend comes out from the shadow". J Physiol 589 (7): 1509–10. PMID 21486835. 
19. ^ Wall BT, Stephens FB, Constantin-Teodosiu D, Marimuthu K, Macdonald IA, Greenhaff PL (2011). "Chronic oral ingestion of L-carnitine and carbohydrate increases muscle carnitine content and alters muscle fuel metabolism during exercise in humans". J Physiol 589 (4): 963–73. PMID 21224234. 
20. ^ 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, Volume 86, No. 6, 1738-1744, December 2007
21. ^ "Toxicity, Valproate: Treatment & Medication". http://emedicine.medscape.com/article/819315-treatment. 
22. ^ Linus Pauling Institute at Oregon State University
23. ^ Linus Pauling Institute at Oregon State University
24. ^ "L-carnitine.(Monograph) - Alternative Medicine Review &#124". HighBeam Research. 2005-03-01. http://www.encyclopedia.com/doc/1G1-131086133.html. Retrieved 2011-03-30. 
25. ^ "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. ^{[dead link]}

External links

• article on Carnitine at University of Maryland Medical Center
• Molecule of the Month at University of Bristol