Carnitine

Carnitine

Systematic (IUPAC) name
3-hydroxy-4-(trimethylazaniumyl)butanoate
Identifiers
CAS number	541-15-1
ATC code	A16AA01
PubChem	CID 288
DrugBank	APRD01070
ChemSpider	282
Chemical data
Formula	C7H15NO3
Mol. mass	161.199 g/mol
SMILES	eMolecules & PubChem
Pharmacokinetic data
Bioavailability	< 10%
Protein binding	None
Metabolism	slightly
Excretion	Urine (> 95%)
Therapeutic considerations
Pregnancy cat.	?
Legal status	?
Routes	oral and iv
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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]

Biochemistry

Production

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 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.

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.

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] L-carnitine supplementation has also shown to have beneficial effects in the treatment of varicocele, a major cause of male infertility. ^[17]

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, 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. " ^[18]

Regular supplements of L-carnitine, however, contribute to energy metabolism and improved neurotransmitter function in the brain in elderly.^[19]

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."^[20] 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).

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.^[22]

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).^[23]

See also

• Acetylcarnitine
• Primary carnitine deficiency

References

External links

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