Carnitine
Carnitine (β-hydroxy-γ-N-trimethylaminobutyric acid, 3-hydroxy-4-N,N,N- trimethylaminobutyrate) is aquaternary ammonium compound[1] involved in metabolism in most mammals, plants and some bacteria.[2] Carnitine may exist in two isomers, labeled D-carnitine and L-carnitine, as they are optically active. At room temperature, pure carnitine is a white powder, and a water-soluble zwitterion with low toxicity. Carnitine only exists in animals as theL-enantiomer, and D-carnitine is toxic because it inhibits the activity of L-carnitine.[3]Carnitine was discovered in 1905 as a result of its high concentration in muscle tissue. It was originally labeled vitamin BT; however, because carnitine is synthesized in the human body, it is no longer considered a vitamin.[2]Carnitine can be synthesized by most humans; about 1 in 350 males is unable to synthesize it due to genetic causes on the X chromosome.[4][5] Carnitine is involved in the oxidation of fatty acids, and involved insystemic primary carnitine deficiency. It has been studied for preventing and treating other conditions, and is used as a purportedperformance enhancing drug.[1]
Biosynthesis and metabolism
Many eukaryotes have the ability to synthesize carnitine, including humans. Humans synthesize carnitine from the substrate TML (6-N-trimethyllysine), which is in turn derived from the methylation of the amino acid lysine. TML is then hydroxylated into hydroxytrimethyllysine (HTML) bytrimethyllysine dioxygenase, requiring the presence of ascorbic acid. HTML is then cleaved by HTML aldose, yielding 4-trimethylaminobutyraldehyde (TMABA) andglycine. TMABA is then dehydrogenated into gamma-butyrobetaine, in an NAD+-dependent reaction, catalyzed by TMABA dehydrogenase. Gamma-butyrobetaine is then hydroxylated by gamma butyrobetaine hydroxylase into L-carnitine, requiring iron in the form of Fe2+.[6]
Carnitine is involved in transporting fatty acids across the mitochondrial membrane, by forming a long chain acetylcarnitine ester and being transported by carnitine palmitoyltransferase I and carnitine palmitoyltransferase II.[7] Carnitine also plays a role in stabilizing Acetyl-CoA and coenzyme A levels through the ability to receive or give an acetyl group.[8]
Physiological effects
Deficiency
Carnitine deficiency caused by a genetic defect in carnitine transport occurs in roughly 1 in 50,000 in the US. Systemic primary carnitine deficiency (SPDC) is characterized by various cardiological, metabolic and musculoskeletal symptoms that vary widely in age of onset and presentation. Prognosis is generally good with carnitine supplementation.[9]
Secondary carnitine deficiency may occur due to conditions such as malnutrition, poor absorption or access to only vegetables.[7]
Supplementation
Some research has been carried out on carnitine supplementation in athletes, given its role in fatty acid metabolism; however, individual responses varied significantly in the 300 people involved in one study.[vague][8]Carnitine has been studied in various cardiometabolic conditions, with a bit of evidence pointing towards efficacy as an adjunct in heart disease and diabetes. However, there are insufficient trials to determine its efficacy.[10] Carnitine has no effect on preventing mortality associated with cardiovascular conditions.[11] Carnitine has no effect on serum lipids, except a possible lowering of LDL[12] Carnitine has no effect on most parameters in end stage kidney disease, however it possibly has an effect on c-reactive protein. The effects on mortality and disease outcome are unknown.[13]
Male infertility
The carnitine content of seminal fluid is directly related to sperm count and motility, suggesting that the compound might be of value in treating male infertility. Several studies indicate that carnitine supplementation (2–3 grams/day for 3–4 months) may improve sperm quality, and one randomized, double-blind crossover trial found that 2 grams/day of carnitine taken for 2 months by 100 infertile men increased the concentration and both total and forward motility of their sperm. The reported benefits may relate to increased mitochondrial fatty-acid oxidation (providing more energy for sperm) and reduced cell death in the testes.
Atherosclerosis
An important interaction between diet and the intestinal microbiome brings into play additional metabolic factors that aggravate atherosclerosis beyond dietary cholesterol. This may help to explain some benefits of the Mediterranean diet. Hazen’s group from the Cleveland Clinic reported that carnitine[14]from animal flesh (four times as much in red meat as in fish or chicken), as well as phosphatidylcholine from egg yolk, are converted by intestinal bacteria to trimethylamine (the compound that causes uremic breath to smell fishy). Trimethylamine is oxidized in the liver to trimethylamine N-oxide (TMAO), which causes atherosclerosis in animal models. Patients in the top quartile of TMAO had a 2.5-fold increase in the 3-year risk of stroke, death, or myocardial infarction.
A key issue is that vegans who consumed L-carnitine did not produce TMAO because they did not have the intestinal bacteria that produce TMA from carnitine.[15]
Sources
Food
Sources of carnitine
Animal products like meat, fish, poultry, and milk are the best sources. In general, the redder the meat, the higher its carnitine content. Dairy products contain carnitine primarily in the whey fraction, in small amounts relative to red meat.[16][17][18] The carnitine content of several foods is listed in Table 1.
Carnitine occurs in two forms, known as D and L, that are mirror images (isomers) of each other. Only L-carnitine is active in the body and is the form found in food [1,6].[19][20][21] However, even strict vegetarians (vegans) show no signs of carnitine deficiency, despite the fact that most dietary carnitine is derived from animal sources.[22][23] No advantage appears to exist in giving an oral dose greater than 2 g at one time, since absorption studies indicatesaturation at this dose.[24]
Health Canada
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). The Canadian government did issue an amendment in December 2011 allowing the sale of L-carnitine without a prescription.[25]
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