Carnitine

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Carnitine
Carnitine.svg
Carnitine ball-and-stick.png
Systematic (IUPAC) name
3-Hydroxy-4-(trimethylazaniumyl)butanoate
Clinical data
AHFS/Drugs.com Micromedex Detailed Consumer Information
Legal status ?
Routes oral and iv
Pharmacokinetic data
Bioavailability < 10%
Protein binding None
Metabolism slightly
Excretion Urine (> 95%)
Identifiers
CAS number 541-15-1 YesY
ATC code A16AA01 (L form)
PubChem CID 288
DrugBank DB00583
ChemSpider 282 YesY
UNII 0G389FZZ9M YesY
KEGG C00318 YesY
ChEBI CHEBI:17126 YesY
ChEMBL CHEMBL172513 YesY
Chemical data
Formula C7H15NO3 
Mol. mass 161.199 g/mol
 N (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 intermembraneous space in the mitochondria, into the mitochondrial matrix during the breakdown of lipids (fats) for the generation of metabolic energy.[2] It is widely available as a nutritional supplement. Carnitine was originally found as a growth factor for mealworms and labeled vitamin BT,[3] although carnitine is not a proper vitamin.[4] Carnitine exists in two stereoisomers: its biologically active form is L-carnitine, whereas its enantiomer, D-carnitine, is biologically inactive.[2][5]

Biochemistry[edit]

Biosynthesis[edit]

In animals, the biosynthesis of carnitine occurs primarily in the liver and kidneys from the amino acids lysine (via trimethyllysine) and methionine.[6] Vitamin C (ascorbic acid) is not essential to the synthesis of carnitine.[7]

Role in fatty acid metabolism[edit]

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.[2] 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.[2] This occurs via a series of similar steps:

  1. Acyl CoA is transferred to the hydroxyl group of 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.[8]

Carnitine acyltransferase I and peroxisomal carnitine octanoyl transferase (CROT) undergo 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[edit]

Atherosclerosis[edit]

There may be a link between dietary consumption of carnitine and atherosclerosis, but there is also evidence that it lowers the risk of mortality and arrythmias after an acute myocardial infarction.

When certain species of intestinal bacteria were exposed to carnitine from food, they produced a waste product, trimethylamine, which is transformed in the liver to trimethylamine N-oxide (TMAO). TMAO may be associated with atherosclerosis. The presence of large amounts of TMAO-producing bacteria was a consequence of a long-term diet rich in meat. However, when the authors compared the risk of cardiovascular events to the levels of carnitine and TMAO, they found that the risk was higher in those with higher TMAO levels, independent of the carnitine levels.

Vegetarian and vegans who ate a single meal of meat had much lower levels of TMAO in their bloodstream than did regular meat-eaters, as vegetarian and vegans had lower levels of the intestinal bacteria that converts carnitine into TMAO.[9]

Effects on bone mass[edit]

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.

Antioxidant effects[edit]

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.[10][citation needed]

Effect on thyroid hormone action[edit]

A 2004 study found that L-carnitine acts as a peripheral antagonist of thyroid hormone action. In particular, L-carnitine inhibits both triiodothyronine (T3) and thyroxine (T4) entry into the cell nuclei.[11]

Possible health effects[edit]

Carnitine has been proposed as a supplement to treat a variety of health conditions including heart attack,[12][13] heart failure, angina,[14] narcolepsy,[15] and diabetic neuropathy,[16] but not fatigue, improving exercise performance,[14] nor wasting syndrome (weight loss),[16]; however, the same source emphasizing that there is no evidence for help with weight loss also claims that "Some studies do show that oral carnitine reduces fat mass, increases muscle mass, and reduces fatigue..". In all of these cases (both positive and negative findings) the results are preliminary, proposed, and not part of routine treatment.[16]

Sources[edit]

Food[edit]

The highest concentrations of carnitine are found in red meat and dairy products. Carnitine can be found at significantly lower levels in many other foods including nuts and seeds (e.g. pumpkin, sunflower, sesame), legumes or pulses (beans, peas, lentils, peanuts), vegetables (artichokes, asparagus, beet greens (young leaves of the beetroot), 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 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[17]
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.[17] 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.[citation needed]

Health Canada[edit]

Other sources may be found in over-the-counter vitamins, energy drinks and various other products. Products containing L-carnitine can now be marketed as "natural health products" in Canada. As of 2012 Parliament has allowed Carnitine products and supplements to be imported into Canada (Health Canada). Canadian government did issue an amendment in December 2011 allowing the sale of L-carnitine without a prescription.[18]

See also[edit]

References[edit]

  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 b c d Mehta, Sweety (2013-10-06). "Activation and transportation of fatty acids to the mitochondria via the carnitine shuttle". Pharmaxchange.info. Retrieved 2014-02-01. 
  3. ^ Carter, H. E.; Bhattacharyya, P. K.; Weidman, K. R.; Fraenkel, G. Chemical studies on vitamin BT. Isolation and characterization as carnitine. Arch. Biochem. Biophys., 1952, 38, 405–416.
  4. ^ Bremer, J. Carnitine - metabolism and functions. Physiol. Rev., 1983, 63, 1420-1480.
  5. ^ 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. 
  6. ^ "L-Carnitine". Archived from the original on 2007-05-08. Retrieved 2007-06-01. 
  7. ^ Furusawa, H; Sato, Y; Tanaka, Y; Inai, Y; Amano, A; Iwama, M; Kondo, Y; Handa, S; Murata, A; Nishikimi, M; Goto, S; Maruyama, N; Takahashi, R; Ishigami, A (September 2008). "Vitamin C is not essential for carnitine biosynthesis in vivo: verification in vitamin C-depleted senescence marker protein-30/gluconolactonase knockout mice.". Biological & Pharmaceutical Bulletin 31 (9): 1673–9. doi:10.1248/bpb.31.1673. PMID 18758058. 
  8. ^ 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. 
  9. ^ Koeth, Robert; et al (2013). "Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis". Nature Medicine 19 (5): 576–85. doi:10.1038/nm.3145. PMC 3650111. PMID 23563705. 
  10. ^ Claudio Cavazza, Composition for the Prevention and Treatment of Osteoporosis due to Menopause Syndrome (2002), US Patent 6,335,038, column 3.
  11. ^ Benvenga S, Amato A, Calvani M, Trimarchi F (Nov 2004). "Effects of carnitine on thyroid hormone action". Ann N Y Acad Sci 1033: 158–167. 
  12. ^ Dinicolantonio, J. J.; Lavie, C. J.; Fares, H.; Menezes, A. R.; o’Keefe, J. H. (2013). "L-Carnitine in the Secondary Prevention of Cardiovascular Disease: Systematic Review and Meta-analysis" (pdf). Mayo Clinic Proceedings. doi:10.1016/j.mayocp.2013.02.007. PMID 23597877.  edit
  13. ^ Marcovina, S. M.; Sirtori, C.; Peracino, A.; Gheorghiade, M.; Borum, P.; Remuzzi, G.; Ardehali, H. (2013). "Translating the basic knowledge of mitochondrial functions to metabolic therapy: Role of L-carnitine". Translational Research 161 (2): 73–84. doi:10.1016/j.trsl.2012.10.006. PMC 3590819. PMID 23138103.  edit
  14. ^ a b Pekala, J.; Patkowska-Sokoła, B.; Bodkowski, R.; Jamroz, D.; Nowakowski, P.; Lochyński, S.; Librowski, T. (2011). "L-carnitine--metabolic functions and meaning in humans life". Current drug metabolism 12 (7): 667–678. doi:10.2174/138920011796504536. PMID 21561431.  edit
  15. ^ Miyagawa, T; Kawamura, H; Obuchi, M; Ikesaki, A; Ozaki, A; Tokunaga, K; Inoue, Y; Honda, M (2013). "Effects of oral L-carnitine administration in narcolepsy patients: A randomized, double-blind, cross-over and placebo-controlled trial". PLoS ONE 8 (1): e53707. doi:10.1371/journal.pone.0053707. PMC 3547955. PMID 23349733.  edit
  16. ^ a b c Ehrlich, SD (2011-03-31). "Carnitine (L-carnitine)". University of Maryland Medical Center. Retrieved 2013-05-01. 
  17. ^ a b "Linus Pauling Institute at Oregon State University". Lpi.oregonstate.edu. Retrieved 2014-02-01. 
  18. ^ "Regulations Amending the Food and Drug Regulations". 

External links[edit]