Choline

Source: Wikipedia, the free encyclopedia.
(Redirected from
Choline salicylate
)
Not to be confused with chlorine.
Choline
Choline cation skeletal formula
Ball-and-stick model
Names
IUPAC name
2-Hydroxyethyl(trimethyl)azanium[1]
Preferred IUPAC name
2-Hydroxy-N,N,N-trimethylethan-1-aminium
Other names
  • Bilineurine
  • (2-Hydroxyethyl)trimethylammonium
  • 2-Hydroxy-N,N,N-trimethylethanaminium
Identifiers
3D model (
JSmol
)
1736748
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard
 100.000.487 Edit this at Wikidata
EC Number
  • 200-535-1
324597
IUPHAR/BPS
KEGG
UNII
  • InChI=1S/C5H14NO/c1-6(2,3)4-5-7/h7H,4-5H2,1-3H3/q+1 checkY
    Key: OEYIOHPDSNJKLS-UHFFFAOYSA-N checkY
  • C[N+](C)(C)CCO
Properties
[(CH3)3NCH2CH2OH]+
Molar mass 104.173 g·mol−1
Appearance Viscous colorless deliquescent liquid (choline hydroxide)[2]
Very soluble (choline hydroxide)[2]
Solubility soluble in
diethylether and chloroform[3]
(choline hydroxide)
Structure
Tetrahedral at the nitrogen atom
Hazards
Occupational safety and health (OHS/OSH):
Main hazards
Corrosive
GHS labelling:
GHS05: Corrosive
Danger
H314
P260, P264, P280, P301+P330+P331, P303+P361+P353, P304+P340, P305+P351+P338, P310, P321, P363, P405, P501
NFPA 704 (fire diamond)
NFPA 704 four-colored diamondHealth (blue): no hazard codeFlammability (red): no hazard codeInstability (yellow): no hazard codeSpecial hazard COR: Corrosive; strong acid or base. E.g. sulfuric acid, potassium hydroxide
COR
Lethal dose or concentration (LD, LC):
3–6 g/kg (rat, oral)[2]
Safety data sheet (SDS) 4
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
checkY verify (what is checkY☒N ?)

Choline (

B vitamin (vitamin B4).[5][6]
It is a structural part of
cation with the chemical formula [(CH3)3NCH2CH2OH]+. Choline forms various salts, for example choline chloride and choline bitartrate
.

Chemistry

Choline is a

viscous hydrated syrup that smells of trimethylamine (TMA). Aqueous solutions of choline are stable, but the compound slowly breaks down to ethylene glycol, polyethylene glycols, and TMA.[2]

Choline chloride can be made by treating TMA with

2-chloroethanol:[2]

(CH3)3N + ClCH2CH2OH → [(CH3)3NCH2CH2OH]+Cl−

The 2-chloroethanol can be generated from ethylene oxide.[how?] Choline has historically been produced from natural sources, such as via hydrolysis of lecithin.[2]

Choline as a nutrient

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

S-adenosyl homocysteine.[5]

Symptomatic choline deficiency causes

American diet.[5][9]

Metabolism

Biosynthesis

Biosynthesis of choline in plants

In plants, the first step in

S-adenosyl-L-homocysteine is generated as a side product.[14]

Main pathways of choline (Chol) metabolism, synthesis and excretion. Click for details. Some of the abbreviations are used in this section.

In humans and most other animals, de novo synthesis of choline is via the

S-adenosylhomocysteines (SAHs) are formed as a byproduct.[8]

Choline can also be released from more complex choline containing molecules. For example,

CDP-choline (CDP-Chol) with cytidine triphosphate (CTP). CDP-choline and diglyceride are transformed to PC by diacylglycerol cholinephosphotransferase (CPT).[8]

In humans, certain PEMT-enzyme

knockout mice, PEMT inactivation makes them completely dependent on dietary choline.[3]

Absorption

In humans, choline is absorbed from the

Gut microbes degrade the unabsorbed choline to trimethylamine, which is oxidized in the liver to trimethylamine N-oxide.[8]

Phosphocholine and

glycerophosphocholines are hydrolyzed via phospholipases to choline, which enters the portal vein. Due to their water solubility, some of them escape unchanged to the portal vein. Fat-soluble choline-containing compounds (phosphatidylcholines and sphingomyelins) are either hydrolyzed by phospholipases or enter the lymph incorporated into chylomicrons.[8]

Transport

In humans, choline is transported as a free molecule in blood. Choline–containing

micromoles per liter (μmol/L) and 10 μmol/L on average. Levels are regulated, but choline intake and deficiency alters these levels. Levels are elevated for about 3 hours after choline consumption. Phosphatidylcholine levels in the plasma of fasting adults is 1.5–2.5 mmol/L. Its consumption elevates the free choline levels for about 8–12 hours, but does not affect phosphatidylcholine levels significantly.[8]

Choline is a water-soluble ion and thus requires transporters to pass through fat-soluble cell membranes. Three types of choline transporters are known:[16]

SLC5A7s are

knockout mice, their dysfunction results easily in death with cyanosis and paralysis.[17]

CTL1s have moderate affinity for choline and transport it in almost all tissues, including the intestines, liver, kidneys,

oxidation of choline to trimethylglycine. CTL1s and CTL2s are not associated with the acetylcholine production, but transport choline together via the blood–brain barrier. Only CTL2s occur on the brain side of the barrier. They also remove excess choline from the neurons back to blood. CTL1s occur only on the blood side of the barrier, but also on the membranes of astrocytes and neurons.[16]

OCT1s and OCT2s are not associated with the acetylcholine production.[8] They transport choline with low affinity. OCT1s transport choline primarily in the liver and kidneys; OCT2s in kidneys and the brain.[16]

Storage

Choline is stored in the cell membranes and organelles as phospholipids, and inside cells as phosphatidylcholines and glycerophosphocholines.[8]

Excretion

Even at choline doses of 2–8 g, little choline is excreted into urine in humans. Excretion happens via transporters that occur within kidneys (see transport). Trimethylglycine is demethylated in the liver and kidneys to

Methylglycine forms, is excreted into urine, or is demethylated to glycine.[8]

Function

Choline and its derivatives have many functions in humans and in other organisms. The most notable function is that choline serves as a synthetic precursor for other essential cell components and signalling molecules, such as phospholipids that form cell membranes, the

S-adenosylmethionine.[18][19]

Phospholipid precursor

Choline is transformed to different phospholipids, like phosphatidylcholines and sphingomyelins. These are found in all cell membranes and the membranes of most cell organelles.[3] Phosphatidylcholines are structurally important part of the cell membranes. In humans 40–50% of their phospholipids are phosphatidylcholines.[8]

Choline phospholipids also form

lipid rafts in the cell membranes along with cholesterol. The rafts are centers, for example for receptors and receptor signal transduction enzymes.[3]

Phosphatidylcholines are needed for the synthesis of

VLDLs: 70–95% of their phospholipids are phosphatidylcholines in humans.[8]

Choline is also needed for the synthesis of pulmonary surfactant, which is a mixture consisting mostly of phosphatidylcholines. The surfactant is responsible for lung elasticity, that is for lung tissue's ability to contract and expand. For example, deficiency of phosphatidylcholines in the lung tissues has been linked to acute respiratory distress syndrome.[20]

Phosphatidylcholines are excreted into

intestinal absorption of lipids.[3]

Acetylcholine synthesis

Choline is needed to produce acetylcholine. This is a neurotransmitter which plays a necessary role in

neural development, for example.[8] Nonetheless, there is little acetylcholine in the human body relative to other forms of choline.[3] Neurons also store choline in the form of phospholipids to their cell membranes for the production of acetylcholine.[8]

Source of trimethylglycine

In humans, choline is

epigenetic regulation. Choline deficiency thus leads to elevated homocysteine levels and decreased SAM levels in blood.[8]

Content in foods

Choline occurs in foods as a free molecule and in the form of phospholipids, especially as phosphatidylcholines. Choline is highest in

adequate intake of 550 mg/day. 100% of the daily value means that a serving of food has 550 mg of choline.[21] "Total choline" is defined as the sum of free choline and choline-containing phospholipids, without accounting for mass fraction.[22][23][8]

kilocalories (kcal) to every infant formula. In the EU, levels above 50 mg/100 kcal are not allowed.[8][24]

Trimethylglycine is a functional

wheat germ (1,240 mg/100 g) and spinach (600–645 mg/100 g), for example.[22]

Choline content of foods (mg/100 g)[a][22]
Meats Vegetables
Bacon, cooked 124.89 Bean, snap 13.46
Beef, trim-cut, cooked 78.15 Beetroot 6.01
Beef liver
, pan fried 		418.22 Broccoli 40.06
Chicken, roasted, with skin 65.83 Brussels sprout 40.61
Chicken, roasted, no skin 78.74 Cabbage 15.45
Chicken liver
 290.03 Carrot 8.79
Cod, atlantic 83.63 Cauliflower 39.10
Ground beef, 75–85% lean, broiled 79.32–82.35 Sweetcorn, yellow 21.95
Pork loin cooked 102.76 Cucumber 5.95
Shrimp, canned 70.60
Lettuce, iceberg
 6.70
Dairy products (cow) Lettuce, romaine 9.92
Butter, salted 18.77 Pea 27.51
Cheese 16.50–27.21 Sauerkraut 10.39
Cottage cheese 18.42 Spinach 22.08
Milk, whole/skimmed 14.29–16.40 Sweet potato 13.11
Sour cream 20.33 Tomato 6.74
Yogurt, plain 15.20 Zucchini 9.36
Grains Fruits
Oat bran, raw 58.57 Apple 3.44
Oats, plain 7.42 Avocado 14.18
Rice, white 2.08 Banana 9.76
Rice, brown 9.22 Blueberry 6.04
Wheat bran 74.39 Cantaloupe 7.58
Wheat germ
, toasted 		152.08 Grape 7.53
Others Grapefruit 5.63
Bean, navy 26.93 Orange 8.38
Egg, chicken
 251.00 Peach 6.10
Olive oil 0.29 Pear 5.11
Peanut 52.47 Prune 9.66
Soybean, raw 115.87 Strawberry 5.65
Tofu, soft 27.37 Watermelon 4.07
  1. ^ Foods are raw unless noted otherwise. Contents are "total choline" as defined above.

Daily values

The following table contains updated sources of choline to reflect the new Daily Value and the new Nutrition Facts and Supplement Facts Labels.[21] It reflects data from the U.S. Department of Agriculture, Agricultural Research Service. FoodData Central, 2019.[21]

Selected Food Sources of Choline[21]
Food Milligrams (mg) per serving Percent DV*
Beef liver
, pan fried, 3 oz (85 g) 		356 65
Egg, hard boiled, 1 large egg 147 27
Beef
top round
, separable lean only, braised, 3 oz (85 g) 		117 21
Soybeans, roasted, 1⁄2 cup 107 19
Chicken breast, roasted, 3 oz (85 g) 72 13
Beef, ground, 93% lean meat, broiled, 3 oz (85 g) 72 13
Cod, Atlantic, cooked, dry heat, 3 oz (85 g) 71 13
Mushrooms, shiitake, cooked, 1⁄2 cup pieces 58 11
Potatoes, red
, baked, flesh and skin, 1 large potato 		57 10
Wheat germ
, toasted, 1 oz (28 g) 		51 9
Beans, kidney, canned, 1⁄2 cup 45 8
Quinoa, cooked, 1 cup 43 8
Milk
, 1% fat, 1 cup 		43 8
Yogurt, vanilla, nonfat, 1 cup 38 7
Brussels sprouts, boiled, 1⁄2 cup 32 6
Broccoli, chopped, boiled, drained, 1⁄2 cup 31 6
Cottage cheese, nonfat, 1 cup 26 5
Tuna, white, canned in water, drained in solids, 3 oz (85 g) 25 5
Peanuts, dry roasted, 1⁄4 cup 24 4
Cauliflower, 1 in (2.5 cm) pieces, boiled, drained, 1⁄2 cup 24 4
Peas, green
, boiled, 1⁄2 cup 		24 4
Sunflower seeds
, oil roasted, 1⁄4 cup 		19 3
Rice, brown, long-grain, cooked, 1 cup 19 3
Bread, pita, whole wheat, 1 large (6+1⁄2 in or 17 cm diameter) 17 3
Cabbage, boiled, 1⁄2 cup 15 3
Tangerine (mandarin orange), sections, 1⁄2 cup 10 2
Beans, snap
, raw, 1⁄2 cup 		8 1
Kiwifruit, raw, 1⁄2 cup sliced 7 1
Carrots, raw, chopped, 1⁄2 cup 6 1
Apples, raw, with skin, quartered or chopped, 1⁄2 cup 2 0

DV = Daily Value. The U.S. Food and Drug Administration (FDA) developed DVs to help consumers compare the nutrient contents of foods and dietary supplements within the context of a total diet. The DV for choline is 550 mg for adults and children age 4 years and older.[25] The FDA does not require food labels to list choline content unless choline has been added to the food. Foods providing 20% or more of the DV are considered to be high sources of a nutrient, but foods providing lower percentages of the DV also contribute to a healthful diet.[21]

The U.S. Department of Agriculture's (USDA's) FoodData Central lists the nutrient content of many foods and provides a comprehensive list of foods containing choline arranged by nutrient content.[21]

Dietary recommendations

Insufficient data is available to establish an estimated average requirement (EAR) for choline, so the Food and Nutrition Board (FNB) established adequate intakes (AIs).[26][27] For adults, the AI for choline was set at 550 mg/day for men and 425 mg/day for women. These values have been shown to prevent hepatic alteration in men. However, the study used to derive these values did not evaluate whether less choline would be effective, as researchers only compared a choline-free diet to a diet containing 550 mg of choline per day. From this, the AIs for children and adolescents were extrapolated.[28][29]

Recommendations are in milligrams per day (mg/day). The

EU countries. The EFSA has not set any upper limits for intake.[8] Individual EU countries may have more specific recommendations. The National Academy of Medicine (NAM) recommendations apply in the United States,[21] Australia and New Zealand.[30]

Choline recommendations (mg/day)
Age EFSA
adequate intake[8]
 US NAM adequate intake[21] US NAM
tolerable upper intake levels[21]
Infants and children
0–6 months Not established 125 Not established
7–12 months 160 150 Not established
1–3 years 140 200 1,000
4–6 years 170 250 1,000
7–8 years 250 250 1,000
9–10 years 250 375 1,000
11–13 years 340 375 2,000
Males
14 years 340 550 3,000
15–18 years 400 550 3,000
19+ years 400 550 3,500
Females
14 years 340 400 3,000
15–18 years 400 400 3,000
19+ y 400 425 3,500
If pregnant 480 450 3,500 (3,000 if ≤18 y)
If breastfeeding 520 550 3,500 (3,000 if ≤18 y)

Intake in populations

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

Signs and symptoms

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

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

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

β-oxidation. Fat metabolism within liver therefore decreases.[33]

Excess intake

Excessive doses of choline can have adverse effects. Daily 8–20 g doses of choline, for example, have been found to cause

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

kidney dysfunction predisposes for cardiovascular diseases, but can also decrease TMA and TMAO excretion.[35]

Health effects

Neural tube closure

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.[citation needed] 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

Choline deficiency can cause

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]

Cognition

Studies observing the effect between higher choline intake and cognition have been conducted in human adults, with contradictory results.[5][40] Similar studies on human infants and children have been contradictory and also limited.[5]

Perinatal development

Both pregnancy and lactation increase demand for choline dramatically. This demand may be met by upregulation of

PEMT via increasing estrogen levels to produce more choline de novo, but even with increased PEMT activity, the demand for choline is still so high that bodily stores are generally depleted. This is exemplified by the observation that Pemt −/− mice (mice lacking functional PEMT) will abort at 9–10 days unless fed supplemental choline.[41]

While maternal stores of choline are depleted during pregnancy and lactation, the placenta accumulates choline by pumping choline against the concentration gradient into the tissue, where it is then stored in various forms, mostly as acetylcholine. Choline concentrations in amniotic fluid can be ten times higher than in maternal blood.[41]

Functions in the fetus

Choline is in high demand during pregnancy as a substrate for building

parturition.[47][48]

Choline uptake into the brain is controlled by a low-affinity transporter located at the blood–brain barrier.[49] Transport occurs when arterial blood plasma choline concentrations increase above 14 μmol/L, which can occur during a spike in choline concentration after consuming choline-rich foods. Neurons, conversely, acquire choline by both high- and low-affinity transporters. Choline is stored as membrane-bound phosphatidylcholine, which can then be used for acetylcholine neurotransmitter synthesis later. Acetylcholine is formed as needed, travels across the synapse, and transmits the signal to the following neuron. Afterwards, acetylcholinesterase degrades it, and the free choline is taken up by a high-affinity transporter into the neuron again.[50]

Uses

Choline

citrate and choline bicarbonate.[2]

Antagonists and inhibitors

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

Discovery

In 1849,

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

In the early 1930s,

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]

References

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