Choline
Choline (/ˈkoʊliːn/ KOH-leen)[4] is an essential nutrient for humans and many other animals, which was formerly classified as a B vitamin (vitamin B4).[5][6] It is a structural part of phospholipids and a methyl donor in metabolic one-carbon chemistry. The compound is related to trimethylglycine in the latter respect. It is a cation with the chemical formula [(CH3)3NCH2CH2OH]+. Choline forms various salts, for example choline chloride and choline bitartrate.
Not to be confused with chlorine.Choline as a nutrient[edit]
Choline is widespread in nature in living beings. In most animals, choline phospholipids are necessary components in cell membranes, in the membranes of cell organelles, and in very low-density lipoproteins.[5]
Choline is an essential nutrient for humans and many other animals.[5][6] Humans are capable of some de novo synthesis of choline but require additional choline in the diet to maintain health. Dietary requirements can be met by choline by itself or in the form of choline phospholipids, such as phosphatidylcholine.[5] Choline is not formally classified as a vitamin despite being an essential nutrient with an amino acid–like structure and metabolism.[3]
Choline is required to produce acetylcholine – a neurotransmitter – and S-adenosylmethionine (SAM), a universal methyl donor. Upon methylation SAM is transformed into S-adenosyl homocysteine.[5]
Symptomatic choline deficiency causes non-alcoholic fatty liver disease and muscle damage.[5] Excessive consumption of choline (greater than 7.5 grams per day) can cause low blood pressure, sweating, diarrhea and fish-like body smell due to trimethylamine, which forms in the metabolism of choline.[5][8] Rich dietary sources of choline and choline phospholipids include organ meats, egg yolks, dairy products, peanuts, certain beans, nuts and seeds. Vegetables with pasta and rice also contribute to choline intake in the American diet.[5][9]
Intake in populations[edit]
Twelve surveys undertaken in 9 EU countries between 2000 and 2011 estimated choline intake of adults in these countries to be 269–468 milligrams per day. Intake was 269–444 mg/day in adult women and 332–468 mg/day in adult men. Intake was 75–127 mg/day in infants, 151–210 mg/day in 1- to 3-year-olds, 177–304 mg/day in 3- to 10-year-olds and 244–373 mg/day in 10- to 18-year-olds. The total choline intake mean estimate was 336 mg/day in pregnant adolescents and 356 mg/day in pregnant women.[8]
A study based on the NHANES 2009–2012 survey estimated the choline intake to be too low in some US subpopulations. Intake was 315.2–318.8 mg/d in 2+ year olds between this time period. Out of 2+ year olds, only 15.6±0.8% of males and 6.1±0.6% of females exceeded the adequate intake (AI). AI was exceeded by 62.9±3.1% of 2- to 3-year-olds, 45.4±1.6% of 4- to 8-year-olds, 9.0±1.0% of 9- to 13-year-olds, 1.8±0.4% of 14–18 and 6.6±0.5% of 19+ year olds. Upper intake level was not exceeded in any subpopulations.[31]
A 2013–2014 NHANES study of the US population found the choline intake of 2- to 19-year-olds to be 256±3.8 mg/day and 339±3.9 mg/day in adults 20 and over. Intake was 402±6.1 mg/d in men 20 and over and 278 mg/d in women 20 and over.[32]
Deficiency[edit]
Signs and symptoms[edit]
Symptomatic choline deficiency is rare in humans. Most obtain sufficient amounts of it from the diet and are able to biosynthesize limited amounts of it via PEMT.[3] Symptomatic deficiency is often caused by certain diseases or by other indirect causes. Severe deficiency causes muscle damage and non-alcoholic fatty liver disease, which may develop into cirrhosis.[33]
Besides humans, fatty liver is also a typical sign of choline deficiency in other animals. Bleeding in the kidneys can also occur in some species. This is suspected to be due to deficiency of choline derived trimethylglycine, which functions as an osmoregulator.[3]
Causes and mechanisms[edit]
Estrogen production is a relevant factor which predisposes individuals to deficiency along with low dietary choline intake. Estrogens activate phosphatidylcholine producing PEMT enzymes. Women before menopause have lower dietary need for choline than men due to women's higher estrogen production. Without estrogen therapy, the choline needs of post-menopausal women are similar to men's. Some single-nucleotide polymorphisms (genetic factors) affecting choline and folate metabolism are also relevant. Certain gut microbes also degrade choline more efficiently than others, so they are also relevant.[33]
In deficiency, availability of phosphatidylcholines in the liver are decreased – these are needed for formation of VLDLs. Thus VLDL-mediated fatty acid transport out of the liver decreases leading to fat accumulation in the liver.[8] Other simultaneously occurring mechanisms explaining the observed liver damage have also been suggested. For example, choline phospholipids are also needed in mitochondrial membranes. Their inavailability leads to the inability of mitochondrial membranes to maintain proper electrochemical gradient, which, among other things, is needed for degrading fatty acids via β-oxidation. Fat metabolism within liver therefore decreases.[33]
Excess intake[edit]
Excessive doses of choline can have adverse effects. Daily 8–20 g doses of choline, for example, have been found to cause low blood pressure, nausea, diarrhea and fish-like body odor. The odor is due to trimethylamine (TMA) formed by the gut microbes from the unabsorbed choline (see trimethylaminuria).[8]
The liver oxidizes TMA to trimethylamine N-oxide (TMAO). Elevated levels of TMA and TMAO in the body have been linked to increased risk of atherosclerosis and mortality. Thus, excessive choline intake has been hypothetized to increase these risks in addition to carnitine, which also is formed into TMA and TMAO by gut bacteria. However, choline intake has not been shown to increase the risk of dying from cardiovascular diseases.[34] It is plausible that elevated TMA and TMAO levels are just a symptom of other underlying illnesses or genetic factors that predispose individuals for increased mortality. Such factors may have not been properly accounted for in certain studies observing TMA and TMAO level related mortality. Causality may be reverse or confounding and large choline intake might not increase mortality in humans. For example, kidney dysfunction predisposes for cardiovascular diseases, but can also decrease TMA and TMAO excretion.[35]
Health effects[edit]
Neural tube closure[edit]
Low maternal intake of choline is associated with an increased risk of neural tube defects. Higher maternal intake of choline is likely associated with better neurocognition/neurodevelopment in children.[36][5] Choline and folate, interacting with vitamin B12, act as methyl donors to homocysteine to form methionine, which can then go on to form SAM (S-adenosylmethionine).[5] SAM is the substrate for almost all methylation reactions in mammals. It has been suggested that disturbed methylation via SAM could be responsible for the relation between folate and NTDs.[37] This may also apply to choline. Certain mutations that disturb choline metabolism increase the prevalence of NTDs in newborns, but the role of dietary choline deficiency remains unclear, as of 2015.[5]
Cardiovascular diseases and cancer[edit]
Choline deficiency can cause fatty liver, which increases cancer and cardiovascular disease risk. Choline deficiency also decreases SAM production, which partakes in DNA methylation – this decrease may also contribute to carcinogenesis. Thus, deficiency and its association with such diseases has been studied.[8] However, observational studies of free populations have not convincingly shown an association between low choline intake and cardiovascular diseases or most cancers.[5][8] Studies on prostate cancer have been contradictory.[38][39]
Uses[edit]
Choline chloride and choline bitartrate are used in dietary supplements. Bitartrate is used more often due to its lower hygroscopicity.[3] Certain choline salts are used to supplement chicken, turkey and some other animal feeds. Some salts are also used as industrial chemicals: for example, in photolithography to remove photoresist.[2] Choline theophyllinate and choline salicylate are used as medicines,[2][51] as well as structural analogs, like methacholine and carbachol.[52] Radiolabeled cholines, like 11C-choline, are used in medical imaging.[53] Other commercially used salts include tricholine citrate and choline bicarbonate.[2]
Antagonists and inhibitors[edit]
Hundreds of choline antagonists and enzyme inhibitors have been developed for research purposes. Aminomethylpropanol is among the first ones used as a research tool. It inhibits choline and trimethylglycine synthesis. It is able to induce choline deficiency that in turn results in fatty liver in rodents. Diethanolamine is another such compound, but also an environmental pollutant. N-cyclohexylcholine inhibits choline uptake primarily in brains. Hemicholinium-3 is a more general inhibitor, but also moderately inhibits choline kinases. More specific choline kinase inhibitors have also been developed. Trimethylglycine synthesis inhibitors also exist: carboxybutylhomocysteine is an example of a specific BHMT inhibitor.[3]
The cholinergic hypothesis of dementia has not only lead to medicinal acetylcholinesterase inhibitors, but also to a variety of acetylcholine inhibitors. Examples of such inhibiting research chemicals include triethylcholine, homocholine and many other N-ethyl derivates of choline, which are false neurotransmitter analogs of acetylcholine. Choline acetyltransferase inhibitors have also been developed.[3]
History[edit]
Discovery[edit]
In 1849, Adolph Strecker was the first to isolate choline from pig bile.[54][55] In 1852, L. Babo and M. Hirschbrunn extracted choline from white mustard seeds and named it sinkaline.[55] In 1862, Strecker repeated his experiment with pig and ox bile, calling the substance choline for the first time after the Greek word for bile, chole, and identifying it with the chemical formula C5H13NO.[56][15] In 1850, Theodore Nicolas Gobley extracted from the brains and roe of carps a substance he named lecithin after the Greek word for egg yolk, lekithos, showing in 1874 that it was a mixture of phosphatidylcholines.[57][58]
In 1865, Oscar Liebreich isolated "neurine" from animal brains.[59][15] The structural formulas of acetylcholine and Liebreich's "neurine" were resolved by Adolf von Baeyer in 1867.[60][55] Later that year "neurine" and sinkaline were shown to be the same substances as Strecker's choline. Thus, Bayer was the first to resolve the structure of choline.[61][62][55] The compound now known as neurine is unrelated to choline.[15]
Discovery as a nutrient[edit]
In the early 1930s, Charles Best and colleagues noted that fatty liver in rats on a special diet and diabetic dogs could be prevented by feeding them lecithin,[15] proving in 1932 that choline in lecithin was solely responsible for this preventive effect.[63] In 1998, the US National Academy of Medicine reported their first recommendations for choline in the human diet.[64]