Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Choline: Difference between pages

{{short description|Chemical compound and essential nutrient}}

{{Distinguish|chlorine}}

{{chembox

|Watchedfields = changed

|verifiedrevid = 477165756

|ImageFile = Choline cation.png

|ImageAlt = Choline cation skeletal formula

|ImageName = Choline cation skeletal formula

|ImageFile1 = Choline-cation-3D-balls.png

|ImageSize1 = 180

|ImageAlt1 = Ball-and-stick model

|IUPACName = 2-Hydroxyethyl(trimethyl)azanium<ref name="pubchem">{{cite web | url=https://pubchem.ncbi.nlm.nih.gov/compound/Choline | title=Choline }}</ref>

|PIN = 2-Hydroxy-''N'',''N'',''N''-trimethylethan-1-aminium

|OtherNames = {{ubl|Bilineurine|(2-Hydroxyethyl)trimethylammonium|2-Hydroxy-''N'',''N'',''N''-trimethylethanaminium}}

|Section1={{Chembox Identifiers

|IUPHAR_ligand = 4551

|Beilstein = 1736748

|CASNo = 62-49-7

|CASNo_Ref = {{cascite|correct|??}}

|ChEBI_Ref = {{ebicite|correct|EBI}}

|ChEBI = 15354

|ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

|ChemSpiderID = 299

|DrugBank_Ref = {{drugbankcite|correct|drugbank}}

|DrugBank = DB00122

|EC_number = 200-535-1

|Gmelin = 324597

|KEGG_Ref = {{keggcite|correct|kegg}}

|KEGG = C00114

|UNII_Ref = {{fdacite|correct|FDA}}

|UNII = N91BDP6H0X

|ChEMBL_Ref = {{ebicite|correct|EBI}}

|ChEMBL = 920

|StdInChI_Ref = {{stdinchicite|correct|chemspider}}

|StdInChI = 1S/C5H14NO/c1-6(2,3)4-5-7/h7H,4-5H2,1-3H3/q+1

|StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

|StdInChIKey = OEYIOHPDSNJKLS-UHFFFAOYSA-N

|PubChem = 305

|SMILES = C[N+](C)(C)CCO

|Section2={{Chembox Properties

|Appearance = Viscous colorless deliquescent liquid (choline hydroxide)<ref name=:2/>

|Formula = {{chem2|[(CH3)3NCH2CH2OH]+}}

|C=5|H=14|N=1|O=1

|Solubility = Very soluble (choline hydroxide)<ref name=:2/>

|SolubleOther = soluble in [[ethanol]],<ref name=:2/> insoluble in [[diethylether]] and [[chloroform]]<ref name=ze/> (choline hydroxide)

|Section3={{Chembox Structure

|Coordination = [[Tetrahedral molecular geometry|Tetrahedral]] at the [[nitrogen]] atom

}}

|Section4={{Chembox Hazards

|ExternalSDS = 4

|LD50 = 3–6 g/kg (rat, oral)<ref name=:2/>

|MainHazards = [[Corrosive]]

|NFPA-S = COR

|GHSPictograms = {{GHS05}}

|GHSSignalWord = Danger

|HPhrases = {{H-phrases|314}}

|PPhrases = {{P-phrases|260|264|280|301+330+331|303+361+353|304+340|305+351+338|310|321|363|405|501}}

}}

}}

'''Choline''' ({{IPAc-en|ˈ|k|oʊ|l|iː|n}} {{respell|KOH|leen}})<ref>{{Cite web|url=https://www.lexico.com/en/definition/choline|archive-url=https://web.archive.org/web/20191024155716/https://www.lexico.com/en/definition/choline|url-status=dead|archive-date=24 October 2019|title=Choline|website=Lexico Dictionaries|access-date=2019-11-09}}</ref> is an [[essential nutrient]] for humans and many other animals, which was formerly classified as a [[B vitamin]] ('''vitamin B₄''').<ref name="lpi">{{cite web|date=February 2015|title=Choline|url=http://lpi.oregonstate.edu/mic/other-nutrients/choline|access-date=11 November 2019|publisher=Micronutrient Information Center, Linus Pauling Institute, Oregon State University}}</ref><ref name="Choline HMDB">{{cite encyclopedia|title=Choline|url=http://www.hmdb.ca/metabolites/hmdb00097|website=Human Metabolome Database|publisher=The Metabolomics Innovation Centre, University of Alberta, Edmonton, Canada|access-date=13 September 2016|date=17 August 2016}}</ref>

It is a structural part of [[phospholipid]]s 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]] {{chem2|[(CH3)3NCH2CH2OH]+}}. Choline forms various [[Salt (chemistry)|salts]], for example [[choline chloride]] and [[choline bitartrate]].

{{Use dmy dates|date=September 2020}}

==Chemistry==

Choline is a [[quaternary ammonium cation]]. The cholines are a family of water-soluble [[quaternary ammonium compound]]s.<ref name="Choline HMDB" /><ref>Britannica, The Editors of Encyclopaedia. "choline". Encyclopedia Britannica, 11 Dec. 2013, https://www.britannica.com/science/choline. Accessed 17 February 2022.</ref> Choline is the parent compound of the cholines class, consisting of [[ethanolamine]] residue having three [[methyl]] groups attached to the same [[nitrogen]] atom.<ref name="pubchem" /> [[Choline hydroxide]] is known as choline base. It is [[hygroscopic]] and thus often encountered as a colorless [[viscous]] hydrated syrup that smells of [[trimethylamine]] (TMA). Aqueous solutions of choline are stable, but the compound slowly breaks down to [[ethylene glycol]], [[polyethylene glycol]]s, and TMA.<ref name=:2>{{Cite book|title=Kirk-Othmer encyclopedia of chemical technology|vauthors=Kirk RE|publisher=John Wiley & Sons|year=2000|isbn=9780471484943|edition=4th|volume=6|pages=100–102|display-authors=etal}}</ref>

Choline chloride can be made by treating TMA with [[2-chloroethanol]]:<ref name=:2/>

:{{chem2|(CH3)3N + ClCH2CH2OH → [(CH3)3NCH2CH2OH]+Cl–}}

The 2-chloroethanol can be generated from either reaction of [[ethene]] with [[hypochlorous acid]] or from [[ethylene oxide]] by addition of [[hydrogen chloride]]. Choline has historically been produced from natural sources, such as via [[hydrolysis]] of [[lecithin]].<ref name=:2/>

==Choline as a nutrient==

Choline is widespread in nature in living beings. In most animals, choline phospholipids are necessary components in [[cell membrane]]s, in the membranes of cell [[organelle]]s, and in [[very low-density lipoprotein]]s.<ref name=lpi/>

Choline is an [[essential nutrient]] for humans and many other animals.<ref name="lpi"/><ref name="Choline HMDB"/> Humans are capable of some [[de novo synthesis|''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 [[phospholipid]]s, such as [[phosphatidylcholine]].<ref name=lpi/> Choline is not formally classified as a [[vitamin]] despite being an essential nutrient with an [[amino acid]]–like structure and metabolism.<ref name=ze/>

Choline is required to produce [[acetylcholine]] – a [[neurotransmitter]] – and [[S-adenosyl methionine|''S''-adenosylmethionine]] (SAM), a universal [[methyl]] donor. Upon methylation SAM is transformed into [[S-adenosyl homocysteine]].<ref name="lpi" />

Symptomatic choline deficiency causes [[non-alcoholic fatty liver disease]] and muscle damage.<ref name=lpi/> Excessive consumption of choline (greater than 7.5 grams per day) can cause [[low blood pressure]], [[sweating]], [[diarrhea]] and [[Fish-odor disease|fish-like body smell]] due to [[trimethylamine]], which forms in the metabolism of choline.<ref name=lpi/><ref name=eu/> Rich dietary sources of choline and choline phospholipids include [[organ meats]], [[egg yolks]], [[dairy products]], [[peanut]]s, certain [[beans]], [[Nut (fruit)|nuts]] and [[seeds]]. [[Vegetables]] with [[pasta]] and [[rice]] also contribute to choline intake in the [[American diet]].<ref name=lpi/><ref>{{Cite web | url=https://ods.od.nih.gov/factsheets/Choline-HealthProfessional/ | title=Office of Dietary Supplements – Choline }}</ref>

{{Use dmy dates|date=September 2020}}

== Metabolism ==

=== Biosynthesis ===

[[File:Choline biosynthesis.svg|thumb|450px|[[Biosynthesis]] of choline in plants]]

In plants, the first step in [[de novo synthesis|''de novo'' biosynthesis]] of choline is the [[decarboxylation]] of [[serine]] into [[ethanolamine]], which is catalyzed by a [[decarboxylase|serine decarboxylase]].<ref name="pmid11461929">{{cite journal | vauthors = Rontein D, Nishida I, Tashiro G, Yoshioka K, Wu WI, Voelker DR, Basset G, Hanson AD | title = Plants synthesize ethanolamine by direct decarboxylation of serine using a pyridoxal phosphate enzyme | journal = The Journal of Biological Chemistry | volume = 276 | issue = 38 | pages = 35523–9 | date = September 2001 | pmid = 11461929 | doi = 10.1074/jbc.M106038200 | doi-access = free }}</ref> The synthesis of choline from ethanolamine may take place in three parallel pathways, where three consecutive ''N''-methylation steps catalyzed by a [[methyl transferase]] are carried out on either the free-base,<ref name="pmid16653153">{{cite journal | vauthors = Prud'homme MP, Moore TS | title = Phosphatidylcholine synthesis in castor bean endosperm : free bases as intermediates | journal = Plant Physiology | volume = 100 | issue = 3 | pages = 1527–35 | date = November 1992 | pmid = 16653153 | pmc = 1075815 | doi = 10.1104/pp.100.3.1527 }}</ref> phospho-bases,<ref name="pmid10799484">{{cite journal | vauthors = Nuccio ML, Ziemak MJ, Henry SA, Weretilnyk EA, Hanson AD | title = cDNA cloning of phosphoethanolamine ''N''-methyltransferase from spinach by complementation in ''Schizosaccharomyces pombe'' and characterization of the recombinant enzyme | journal = The Journal of Biological Chemistry | volume = 275 | issue = 19 | pages = 14095–101 | date = May 2000 | pmid = 10799484 | doi = 10.1074/jbc.275.19.14095 | doi-access = free }}</ref> or phosphatidyl-bases.<ref name="pmid11481443">{{cite journal | vauthors = McNeil SD, Nuccio ML, Ziemak MJ, Hanson AD | title = Enhanced synthesis of choline and glycine betaine in transgenic tobacco plants that overexpress phosphoethanolamine N-methyltransferase | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 17 | pages = 10001–5 | date = August 2001 | pmid = 11481443 | pmc = 55567 | doi = 10.1073/pnas.171228998 | bibcode = 2001PNAS...9810001M | doi-access = free }}</ref> The source of the methyl group is [[S-adenosyl-L-methionine|''S''-adenosyl-{{sc|L}}-methionine]] and [[S-adenosyl-L-homocysteine|''S''-adenosyl-{{sc|L}}-homocysteine]] is generated as a side product.<ref>{{cite web | title = Superpathway of choline biosynthesis | url = https://biocyc.org/META/NEW-IMAGE?object=PWY-4762 | work = BioCyc Database Collection: MetaCyc | publisher = SRI International }}</ref>

[[File:Choline metabolism.svg|thumb|300px|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 [[phosphatidylethanolamine N-methyltransferase]] (PEMT) pathway,<ref name=eu/> but biosynthesis is not enough to meet human requirements.<ref name=his/> In the hepatic PEMT route, [[3-phosphoglycerate]] (3PG) receives 2 [[acyl group]]s from [[acyl-CoA]] forming a [[phosphatidic acid]]. It reacts with [[cytidine triphosphate]] to form cytidine diphosphate-diacylglycerol. Its [[hydroxyl group]] reacts with serine to form [[phosphatidylserine]] which [[decarboxylate]]s to ethanolamine and [[phosphatidylethanolamine]] (PE) forms. A PEMT enzyme moves three [[methyl]] groups from three [[S-adenosyl methionine|''S''-adenosyl methionines]] (SAM) donors to the ethanolamine group of the phosphatidylethanolamine to form choline in the form of a phosphatidylcholine. Three [[S-adenosyl homocysteine|''S''-adenosylhomocysteines]] (SAHs) are formed as a byproduct.<ref name=eu/>

Choline can also be released from more complex choline containing molecules. For example, [[phosphatidylcholine]]s (PC) can be hydrolyzed to choline (Chol) in most cell types. Choline can also be produced by the CDP-choline route, [[cytosolic]] [[choline kinase]]s (CK) phosphorylate choline with [[Adenosine triphosphate|ATP]] to [[phosphocholine]] (PChol).<ref name=ze/> This happens in some cell types like liver and kidney. [[Choline-phosphate cytidylyltransferase]]s (CPCT) transform PChol to [[CDP-choline]] (CDP-Chol) with cytidine triphosphate (CTP). CDP-choline and [[diglyceride]] are transformed to PC by [[diacylglycerol cholinephosphotransferase]] (CPT).<ref name=eu/>

In humans, certain PEMT-enzyme [[mutation]]s and [[estrogen deficiency]] (often due to [[menopause]]) increase the dietary need for choline. In rodents, 70% of phosphatidylcholines are formed via the PEMT route and only 30% via the CDP-choline route.<ref name=eu/> In [[knockout mice]], PEMT inactivation makes them completely dependent on dietary choline.<ref name=ze/>

=== Absorption ===

In humans, choline is absorbed from the [[intestine]]s via the [[SLC44A1]] (CTL1) [[membrane protein]] via [[facilitated diffusion]] governed by the choline concentration gradient and the electrical potential across the [[enterocyte]] membranes. SLC44A1 has limited ability to transport choline: at high concentrations part of it is left unabsorbed. Absorbed choline leaves the enterocytes via the [[portal vein]], passes the liver and enters [[systemic circulation]]. [[Gut microbe]]s degrade the unabsorbed choline to trimethylamine, which is oxidized in the liver to [[trimethylamine N-oxide|trimethylamine ''N''-oxide]].<ref name=eu/>

Phosphocholine and [[glycerophosphocholine]]s are hydrolyzed via [[phospholipase]]s 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 [[sphingomyelin]]s) are either hydrolyzed by phospholipases or enter the [[lymph]] incorporated into [[chylomicron]]s.<ref name=eu/>

=== Transport ===

In humans, choline is transported as a free molecule in blood. Choline–containing [[phospholipid]]s and other substances, like glycerophosphocholines, are transported in blood [[lipoprotein]]s. [[Blood plasma]] choline levels in healthy [[fasting]] adults is 7–20&nbsp;[[micromoles]] per liter (μmol/L) and 10&nbsp;μmol/L on average. Levels are regulated, but choline intake and deficiency alters these levels. Levels are elevated for about 3&nbsp;hours after choline consumption. Phosphatidylcholine levels in the plasma of fasting adults is 1.5–2.5&nbsp;mmol/L. Its consumption elevates the free choline levels for about 8–12&nbsp;hours, but does not affect phosphatidylcholine levels significantly.<ref name=eu/>

Choline is a water-soluble [[ion]] and thus requires transporters to pass through fat-soluble [[cell membrane]]s. Three types of choline transporters are known:<ref name="Inazu_2019" />

* [[SLC5A7]]

* CTLs: CTL1 ([[SLC44A1]]), CTL2 ([[SLC44A2]]) and CTL4 ([[SLC44A4]])

* OCTs: OCT1 ([[SLC22A1]]) and OCT2 ([[SLC22A2]])

SLC5A7s are [[sodium]]- (Na⁺) and ATP-dependent transporters.<ref name="Inazu_2019">{{cite journal | vauthors = Inazu M | title = Functional Expression of Choline Transporters in the Blood-Brain Barrier | journal = Nutrients | volume = 11 | issue = 10 | pages = 2265 | date = September 2019 | pmid = 31547050 | pmc = 6835570 | doi = 10.3390/nu11102265 | doi-access = free }}</ref><ref name=eu/> They have high [[binding affinity]] for choline, transport it primarily to [[neuron]]s and are indirectly associated with the [[acetylcholine]] production.<ref name=eu/> Their deficient function causes [[hereditary]] weakness in the pulmonary and other muscles in humans via acetylcholine deficiency. In [[knockout mice]], their dysfunction results easily in death with [[cyanosis]] and [[paralysis]].<ref>{{cite journal | vauthors = Barwick KE, Wright J, Al-Turki S, McEntagart MM, Nair A, Chioza B, Al-Memar A, Modarres H, Reilly MM, Dick KJ, Ruggiero AM, Blakely RD, Hurles ME, Crosby AH | display-authors = 6 | title = Defective presynaptic choline transport underlies hereditary motor neuropathy | journal = American Journal of Human Genetics | volume = 91 | issue = 6 | pages = 1103–7 | date = December 2012 | pmid = 23141292 | pmc = 3516609 | doi = 10.1016/j.ajhg.2012.09.019 }}</ref>

CTL1s have moderate affinity for choline and transport it in almost all tissues, including the intestines, liver, kidneys, [[placenta]] and [[mitochondria]]. CTL1s supply choline for phosphatidylcholine and [[trimethylglycine]] production.<ref name=eu/> CTL2s occur especially in the mitochondria in the tongue, kidneys, muscles and heart. They are associated with the mitochondrial [[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 [[astrocyte]]s and neurons.<ref name="Inazu_2019" />

OCT1s and OCT2s are not associated with the acetylcholine production.<ref name=eu/> They transport choline with low affinity. OCT1s transport choline primarily in the liver and kidneys; OCT2s in kidneys and the brain.<ref name="Inazu_2019" />

=== Storage ===

Choline is stored in the cell membranes and [[organelle]]s as phospholipids, and inside cells as phosphatidylcholines and glycerophosphocholines.<ref name=eu/>

=== Excretion ===

Even at choline doses of 2–8&nbsp;g, little choline is excreted into urine in humans. Excretion happens via transporters that occur within kidneys (see [[Choline#Transport|transport]]). Trimethylglycine is demethylated in the liver and kidneys to [[dimethylglycine]] ([[tetrahydrofolate]] receives one of the methyl groups). [[Methylglycine]] forms, is excreted into urine, or is demethylated to [[glycine]].<ref name=eu/>

== 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 [[neurotransmitter]] acetylcholine, and the [[osmoregulator]] [[trimethylglycine]] ([[betaine]]). Trimethylglycine in turn serves as a source of [[methyl group]]s by participating in the biosynthesis of [[S-adenosylmethionine|''S''-adenosylmethionine]].<ref>{{cite journal | vauthors = Glier MB, Green TJ, Devlin AM | title = Methyl nutrients, DNA methylation, and cardiovascular disease | journal = Molecular Nutrition & Food Research | volume = 58 | issue = 1 | pages = 172–82 | date = January 2014 | pmid = 23661599 | doi = 10.1002/mnfr.201200636 | doi-access = free }}</ref><ref name="pmid8333583">{{cite journal | vauthors = Barak AJ, Beckenhauer HC, Junnila M, Tuma DJ | title = Dietary betaine promotes generation of hepatic ''S''-adenosylmethionine and protects the liver from ethanol-induced fatty infiltration | journal = Alcoholism: Clinical and Experimental Research | volume = 17 | issue = 3 | pages = 552–5 | date = June 1993 | pmid = 8333583 | doi = 10.1111/j.1530-0277.1993.tb00798.x}}</ref>

=== 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.<ref name=ze/> Phosphatidylcholines are structurally important part of the cell membranes. In humans 40–50% of their phospholipids are phosphatidylcholines.<ref name=eu/>

Choline phospholipids also form [[lipid rafts]] in the cell membranes along with [[cholesterol]]. The rafts are centers, for example for [[Receptor (biochemistry)|receptors]] and receptor [[signal transduction]] enzymes.<ref name=ze/>

Phosphatidylcholines are needed for the synthesis of [[VLDL]]s: 70–95% of their phospholipids are phosphatidylcholines in humans.<ref name=eu/>

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]].<ref>{{cite journal | vauthors = Dushianthan A, Cusack R, Grocott MP, Postle AD | title = Abnormal liver phosphatidylcholine synthesis revealed in patients with acute respiratory distress syndrome | journal = Journal of Lipid Research | volume = 59 | issue = 6 | pages = 1034–1045 | date = June 2018 | pmid = 29716960 | pmc = 5983399 | doi = 10.1194/jlr.P085050 |doi-access=free }}</ref>

Phosphatidylcholines are excreted into [[bile]] and work together with [[bile acid]] salts as [[surfactant]]s in it, thus helping with the [[intestinal]] absorption of [[lipid]]s.<ref name=ze/>

=== Acetylcholine synthesis ===

Choline is needed to produce acetylcholine. This is a neurotransmitter which plays a necessary role in [[muscle contraction]], memory and [[neural development]], for example.<ref name=eu/> Nonetheless, there is little acetylcholine in the human body relative to other forms of choline.<ref name=ze/> Neurons also store choline in the form of phospholipids to their cell membranes for the production of acetylcholine.<ref name=eu/>

=== Source of trimethylglycine ===

In humans, choline is [[oxidized]] irreversibly in liver mitochondria to [[glycine betaine aldehyde]] by [[choline oxidase]]s. This is oxidized by mitochondrial or cytosolic [[betaine-aldehyde dehydrogenase]]s to trimethylglycine.<ref name=eu/> Trimethylglycine is a necessary osmoregulator. It also works as a substrate for the [[BHMT]]-enzyme, which methylates [[homocysteine]] to [[methionine]]. This is a ''S''-adenosylmethionine (SAM) precursor. SAM is a common reagent in biological [[methylation]] reactions. For example, it methylates [[guanidine]]s of [[DNA]] and certain [[lysine]]s of [[histone]]s. Thus it is part of [[gene expression]] and [[epigenetic regulation]]. Choline deficiency thus leads to elevated homocysteine levels and decreased SAM levels in blood.<ref name=eu/>

== Content in foods ==

Choline occurs in foods as a free molecule and in the form of phospholipids, especially as phosphatidylcholines. Choline is highest in [[organ meats]] and [[egg yolks]] though it is found to a lesser degree in non-organ meats, grains, vegetables, fruit and [[dairy products]]. [[Cooking oil]]s and other food fats have about 5&nbsp;mg/100&nbsp;g of total choline.<ref name=eu>{{Cite journal|date=2016|title=Dietary reference values for choline|journal=EFSA Journal|volume=14|issue=8|doi=10.2903/j.efsa.2016.4484|doi-access=free|quote=In this Opinion, the Panel considers dietary choline including choline compounds (e.g. glycerophosphocholine, phosphocholine, phosphatidylcholine, sphingomyelin).}}</ref> In the United States, [[Nutrition facts label|food labels]] express the amount of choline in a serving as a percentage of [[daily value]] (%DV) based on the [[adequate intake]] of 550&nbsp;mg/day. 100% of the daily value means that a serving of food has 550&nbsp;mg of choline.<ref name="us"/> "Total choline" is defined as the sum of free choline and choline-containing phospholipids, without accounting for mass fraction.<ref name="Zeisel_2003"/><ref name="USDA_2008">{{cite journal |title=USDA Database for the Choline Content of Common Foods, Release 2 |url=https://data.nal.usda.gov/dataset/usda-database-choline-content-common-foods-release-2-2008 |date=January 2008 |doi=10.15482/USDA.ADC/1178141 |language=en |quote=Total choline content was calculated as the sum of Cho, GPC, Pcho, Ptdcho, and SM. |last1=Patterson |first1=Kristine Y. |last2=Bhagwat |first2=Seema A. |last3=Williams |first3=Juhi R. |last4=Howe |first4=Juliette C. |last5=Holden |first5=Joanne M. |last6=Zeisel |first6=Steven H. |last7=Dacosta |first7=Kerry A. |last8=Mar |first8=Mei-Heng |publisher=Nutrient Data Laboratory, Beltsville Human Nutrition Research Center, ARS, USDA }}</ref><ref name=eu/>

[[Human breast milk]] is rich in choline. Exclusive [[breastfeeding]] corresponds to about 120&nbsp;mg of choline per day for the baby. Increase in a mother's choline intake raises the choline content of breast milk and low intake decreases it.<ref name="eu"/> [[Infant formula]]s may or may not contain enough choline. In the EU and the US, it is mandatory to add at least 7&nbsp;mg of choline per 100&nbsp;[[kilocalories]] (kcal) to every infant formula. In the EU, levels above 50&nbsp;mg/100&nbsp;kcal are not allowed.<ref name=eu/><ref>{{cite web|url=https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=107.100|title=21 CFR 107.100: Infant formula; Nutrient requirements; Nutrient specifications; Choline content|publisher=Code of Federal Regulations, Title 21; Food and Drug Administration|date=1 April 2019|access-date=2019-10-24}}</ref>

Trimethylglycine is a functional [[metabolite]] of choline. It substitutes for choline nutritionally, but only partially.<ref name=ze/> High amounts of trimethylglycine occur in [[wheat bran]] (1,339&nbsp;mg/100&nbsp;g), toasted [[wheat germ]] (1,240&nbsp;mg/100&nbsp;g) and [[spinach]] (600–645&nbsp;mg/100&nbsp;g), for example.<ref name="Zeisel_2003">{{cite journal | vauthors = Zeisel SH, Mar MH, Howe JC, Holden JM | title = Concentrations of choline-containing compounds and betaine in common foods | journal = The Journal of Nutrition | volume = 133 | issue = 5 | pages = 1302–7 | date = May 2003 | pmid = 12730414 | doi = 10.1093/jn/133.5.1302 | url = https://www.researchgate.net/publication/10775683 | doi-access = free }}</ref>

{| class="wikitable"

|+Choline content of foods (mg/100&nbsp;g){{efn|name=cholinecontent_table|Foods are raw unless noted otherwise. Contents are "total choline" as defined above.}}<ref name="Zeisel_2003"/>

! colspan="2" |Meats

! colspan="2" |Vegetables

|-

|[[Bacon]], cooked

|124.89

|[[Green bean|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

|-

|[[Atlantic cod|Cod, atlantic]]

|83.63

|[[Cauliflower]]

|39.10

|-

|[[Ground beef]], 75–85% lean, broiled

|79.32–82.35

|[[Maize|Sweetcorn]], yellow

|21.95

|-

|[[Pork loin]] cooked

|102.76

|[[Cucumber]]

|5.95

|-

|[[Shrimp]], canned

|70.60

|[[Lettuce, iceberg]]

|6.70

|-

! colspan="2" |Dairy products (cow)

|[[Romaine lettuce|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

|-

! colspan="2" |Grains

! colspan="2" |Fruits

|-

|Oat [[bran]], raw

|58.57

|[[Apple]]

|3.44

|-

|[[Oatmeal|Oats]], plain

|7.42

|[[Avocado]]

|14.18

|-

|[[White rice|Rice, white]]

|2.08

|[[Banana]]

|9.76

|-

|[[Brown rice|Rice, brown]]

|9.22

|[[Blueberry]]

|6.04

|-

|Wheat [[bran]]

|74.39

|[[Cantaloupe]]

|7.58

|-

|[[Wheat germ]], toasted

|152.08

|[[Grape]]

|7.53

|-

! colspan="2" |Others

|[[Grapefruit]]

|5.63

|-

|[[Navy bean|Bean, navy]]

|26.93

|Orange

|8.38

|-

|[[Chicken egg|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

|}

{{notelist}}

=== Daily values ===

{{cleanup section|reason=Should be merged to above list. The overlaps are quite large to the extent that the values (when converted to 100g) are virtually identical. DV calculation is quite trivial, so this isn't adding anything useful for now.|date=September 2022}}

The following table contains updated sources of choline to reflect the new Daily Value and the new Nutrition Facts and Supplement Facts Labels.<ref name=us /> It reflects data from the U.S. Department of Agriculture, Agricultural Research Service. FoodData Central, 2019.<ref name=us />

{| class="wikitable"

|+Selected Food Sources of Choline<ref name=us />

| Food

| Milligrams (mg) per serving

| Percent DV*

|-

| [[Beef liver]], pan fried, {{cvt|3|oz}}

| 356

| 65

|-

| Egg, hard boiled, 1 large egg

| 147

| 27

|-

| Beef [[top round]], separable lean only, braised, {{cvt|3|oz}}

| 117

| 21

|-

| [[Soybean]]s, roasted, {{frac|1|2}} cup

| 107

| 19

|-

| Chicken breast, roasted, {{cvt|3|oz}}

| 72

| 13

|-

| Beef, ground, 93% lean meat, broiled, {{cvt|3|oz}}

| 72

| 13

|-

| [[Atlantic cod|Cod, Atlantic]], cooked, dry heat, {{cvt|3|oz}}

| 71

| 13

|-

| [[Shiitake|Mushrooms, shiitake]], cooked, {{frac|1|2}} cup pieces

| 58

| 11

|-

| [[Red potato|Potatoes, red]], baked, flesh and skin, 1 large potato

| 57

| 10

|-

| [[Wheat germ]], toasted, {{cvt|1|oz}}

| 51

| 9

|-

| [[Kidney bean|Beans, kidney]], canned, {{frac|1|2}} cup

| 45

| 8

|-

| [[Quinoa]], cooked, 1 cup

| 43

| 8

|-

| [[Cow's milk|Milk]], 1% fat, 1 cup

| 43

| 8

|-

| [[Yogurt]], vanilla, nonfat, 1 cup

| 38

| 7

|-

| [[Brussels sprout]]s, boiled, {{frac|1|2}} cup

| 32

| 6

|-

| [[Broccoli]], chopped, boiled, drained, {{frac|1|2}} cup

| 31

| 6

|-

| [[Cottage cheese]], nonfat, 1 cup

| 26

| 5

|-

| [[Tuna]], white, canned in water, drained in solids, {{cvt|3|oz}}

| 25

| 5

|-

| [[Peanut]]s, dry roasted, {{frac|1|4}} cup

| 24

| 4

|-

| [[Cauliflower]], {{cvt|1|in|cm|1}} pieces, boiled, drained, {{frac|1|2}} cup

| 24

| 4

|-

| [[Green peas|Peas, green]], boiled, {{frac|1|2}} cup

| 24

| 4

|-

| [[Sunflower seeds]], oil roasted, {{frac|1|4}} cup

| 19

| 3

|-

| [[Brown rice|Rice, brown]], long-grain, cooked, 1 cup

| 19

| 3

|-

| [[Pita|Bread, pita]], whole wheat, 1 large ({{cvt|6+1/2|in|cm|0|disp=or}} diameter)

| 17

| 3

|-

| [[Cabbage]], boiled, {{frac|1|2}} cup

| 15

| 3

|-

| [[Tangerine]] ([[mandarin orange]]), sections, {{frac|1|2}} cup

| 10

| 2

|-

| [[Snap bean|Beans, snap]], raw, {{frac|1|2}} cup

| 8

| 1

|-

| [[Kiwifruit]], raw, {{frac|1|2}} cup sliced

| 7

| 1

|-

| Carrots, raw, chopped, {{frac|1|2}} cup

| 6

| 1

|-

| [[Apple]]s, raw, with skin, quartered or chopped, {{frac|1|2}} cup

| 2

| 0

|}

<small>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&nbsp;mg for adults and children age 4 years and older.<ref>{{Cite web|title=Role of choline in human nutrition|url=https://supplement.tools/en/articles/choline|date=15 March 2024|publisher=Supplements List}}</ref> 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.<ref name=us /></small>

<small>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.<ref name=us /></small>

==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).<ref>{{Cite web |title=Office of Dietary Supplements – Choline |url=https://ods.od.nih.gov/factsheets/Choline-HealthProfessional/ |access-date=2023-01-07 |website=ods.od.nih.gov |language=en}}</ref><ref>{{cite report |author1=Institute of Medicine |author-link1=National Academy of Medicine |author2=Food and Nutrition Board |author-link2=Food and Nutrition Board |author3=Standing Committee on the Scientific Evaluation of Dietary Reference Intakes and its Panel on Folate, Other B Vitamins, and Choline and Subcommittee on Upper Reference Levels of Nutrients |year=1998 |title=Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline |pages=390–422 |location=[[District of Columbia]] |publisher=[[National Academies Press]] |doi=10.17226/6015 |isbn=978-0-309-13269-5 |lccn=2000028380 |url=https://nap.nationalacademies.org/catalog/6015/dietary-reference-intakes-for-thiamin-riboflavin-niacin-vitamin-b6-folate-vitamin-b12-pantothenic-acid-biotin-and-choline}}</ref> For adults, the AI for choline was set at 550&nbsp;mg/day for men and 425&nbsp;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&nbsp;mg of choline per day. From this, the AIs for children and adolescents were extrapolated.<ref>{{Cite journal |last1=Wiedeman |first1=Alejandra M. |last2=Barr |first2=Susan I. |last3=Green |first3=Timothy J. |last4=Xu |first4=Zhaoming |last5=Innis |first5=Sheila M. |last6=Kitts |first6=David D. |date=2018-10-16 |title=Dietary Choline Intake: Current State of Knowledge Across the Life Cycle |journal=Nutrients |volume=10 |issue=10 |pages=1513 |doi=10.3390/nu10101513 |issn=2072-6643 |pmc=6213596 |pmid=30332744|doi-access=free }}</ref><ref>{{Cite journal |last1=Zeisel |first1=S. H. |last2=Da Costa |first2=K. A. |last3=Franklin |first3=P. D. |last4=Alexander |first4=E. A. |last5=Lamont |first5=J. T. |last6=Sheard |first6=N. F. |last7=Beiser |first7=A. |date=April 1991 |title=Choline, an essential nutrient for humans |url=https://cdr.lib.unc.edu/downloads/00000840m |journal=FASEB Journal |volume=5 |issue=7 |pages=2093–2098 |doi=10.1096/fasebj.5.7.2010061 |doi-access=free |issn=0892-6638 |pmid=2010061|s2cid=12393618 }}</ref>

Recommendations are in milligrams per day (mg/day). The [[European Food Safety Authority]] (EFSA) recommendations are general recommendations for the [[EU countries]]. The EFSA has not set any upper limits for intake.<ref name="eu" /> Individual EU countries may have more specific recommendations. The [[National Academy of Medicine]] (NAM) recommendations apply in the United States,<ref name="us">{{Cite web|url=https://ods.od.nih.gov/factsheets/Choline-HealthProfessional/|title=Choline|website=Office of Dietary Supplements (ODS) at the National Institutes of Health |access-date=2020-05-19}} {{PD-notice}}</ref> Australia and New Zealand.<ref>{{Cite web|url=https://www.nrv.gov.au/nutrients/choline|title=Choline|last=Choline|date=2014-03-17|website=www.nrv.gov.au|access-date=2019-10-22}}</ref>

{| class="wikitable" style="text-align:center"

|+Choline recommendations (mg/day)

|-

! Age

! EFSA [[adequate intake]]<ref name=eu/>

! US NAM adequate intake<ref name=us/>

! US NAM [[tolerable upper intake levels]]<ref name=us/>

|-

| colspan="4" |'''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

|-

| colspan="4" |'''Males'''

|-

|14 years

|340

|550

|3,000

|-

|15–18 years

|400

|550

|3,000

|-

|19+ years

|400

|550

|3,500

|-

| colspan="4" |'''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&nbsp;mg/day in adult women and 332–468&nbsp;mg/day in adult men. Intake was 75–127&nbsp;mg/day in infants, 151–210&nbsp;mg/day in 1- to 3-year-olds, 177–304&nbsp;mg/day in 3- to 10-year-olds and 244–373&nbsp;mg/day in 10- to 18-year-olds. The total choline intake mean estimate was 336&nbsp;mg/day in pregnant adolescents and 356&nbsp;mg/day in pregnant women.<ref name=eu/>

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&nbsp;mg/d in 2+ year olds between this time period. Out of 2+ year olds, only {{val|15.6|0.8}}% of males and {{val|6.1|0.6}}% of females exceeded the adequate intake (AI). AI was exceeded by {{val|62.9|3.1}}% of 2- to 3-year-olds, {{val|45.4|1.6}}% of 4- to 8-year-olds, {{val|9.0|1.0}}% of 9- to 13-year-olds, {{val|1.8|0.4}}% of 14–18 and {{val|6.6|0.5}}% of 19+ year olds. Upper intake level was not exceeded in any subpopulations.<ref>{{cite journal | vauthors = Wallace TC, Fulgoni VL | title = Assessment of Total Choline Intakes in the United States | journal = Journal of the American College of Nutrition | volume = 35 | issue = 2 | pages = 108–12 | date = 2016 | pmid = 26886842 | doi = 10.1080/07315724.2015.1080127 | s2cid = 24063121 }}</ref>

A 2013–2014 NHANES study of the US population found the choline intake of 2- to 19-year-olds to be {{val|256|3.8}}&nbsp;mg/day and {{val|339|3.9}}&nbsp;mg/day in adults 20 and over. Intake was {{val|402|6.1}}&nbsp;mg/d in men 20 and over and 278&nbsp;mg/d in women 20 and over.<ref>{{Cite web|url=https://www.ars.usda.gov/ARSUserFiles/80400530/pdf/1314/Table_1_NIN_GEN_13.pdf|title=What We Eat in America, NHANES 2013–2014|access-date=2019-10-24}}</ref>

==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 [[Phosphatidylethanolamine N-methyltransferase|PEMT]].<ref name=ze>{{Cite book|title=Handbook of vitamins |url=https://archive.org/details/handbookvitamins00jzem |url-access=limited |vauthors= Rucker RB, Zempleni J, Suttie JW, McCormick DB |publisher=Taylor & Francis |year=2007 |isbn=9780849340222 |edition=4th |pages=[https://archive.org/details/handbookvitamins00jzem/page/n471 459]–477 }}</ref> 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]].<ref name="Corbin_2012">{{cite journal | vauthors = Corbin KD, Zeisel SH | title = Choline metabolism provides novel insights into nonalcoholic fatty liver disease and its progression | journal = Current Opinion in Gastroenterology | volume = 28 | issue = 2 | pages = 159–65 | date = March 2012 | pmid = 22134222 | pmc = 3601486 | doi = 10.1097/MOG.0b013e32834e7b4b }}</ref>

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.<ref name=ze/>

===Causes and mechanisms===

[[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 polymorphism]]s (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.<ref name="Corbin_2012" />

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.<ref name=eu/> 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.<ref name="Corbin_2012" />

==Excess intake==

Excessive doses of choline can have adverse effects. Daily 8–20&nbsp;g doses of choline, for example, have been found to cause [[low blood pressure]], [[nausea]], [[diarrhea]] and [[Fish-odor disease|fish-like body odor]]. The odor is due to trimethylamine (TMA) formed by the gut microbes from the unabsorbed choline (see [[trimethylaminuria]]).<ref name=eu/>

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 disease]]s.<ref name= "DiNicolantonio_2019" >{{cite journal | vauthors = DiNicolantonio JJ, McCarty M, OKeefe J | title = Association of moderately elevated trimethylamine ''N''-oxide with cardiovascular risk: is TMAO serving as a marker for hepatic insulin resistance | journal = Open Heart | volume = 6 | issue = 1 | pages = e000890 | date = 2019 | pmid = 30997120 | pmc = 6443140 | doi = 10.1136/openhrt-2018-000890 }}</ref> 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.<ref>{{cite journal | vauthors = Jia J, Dou P, Gao M, Kong X, Li C, Liu Z, Huang T | title = Assessment of Causal Direction Between Gut Microbiota-Dependent Metabolites and Cardiometabolic Health: A Bidirectional Mendelian Randomization Analysis | journal = Diabetes | volume = 68 | issue = 9 | pages = 1747–1755 | date = September 2019 | pmid = 31167879 | doi = 10.2337/db19-0153 | doi-access = free }}</ref>

==Health effects==

===Neural tube closure===

Low maternal intake of choline is associated with an increased risk of [[neural tube defect]]s. Higher maternal intake of choline is likely associated with better neurocognition/neurodevelopment in children.<ref>{{cite journal |last1=Obeid |first1=Rima |last2=Derbyshire |first2=Emma |last3=Schön |first3=Christiane |title=Association between Maternal Choline, Fetal Brain Development, and Child Neurocognition: Systematic Review and Meta-Analysis of Human Studies |journal=Advances in Nutrition |date=30 August 2022 |volume=13 |issue=6 |pages=2445–2457 |doi=10.1093/advances/nmac082|pmid=36041182 |pmc=9776654 }}</ref><ref name=lpi/> Choline and folate, interacting with [[Vitamin B12|vitamin B₁₂]], act as methyl donors to homocysteine to form methionine, which can then go on to form SAM (''S''-adenosylmethionine).<ref name=lpi/> 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.<ref>{{Cite journal|display-authors=et al|vauthors=Imbard A|date=2013|title=Neural tube defects, folic acid and methylation|journal=International Journal of Environmental Research and Public Health|volume=10|issue=9|pages=4352–4389|doi=10.3390/ijerph10094352|pmc=3799525|pmid=24048206|doi-access=free}}</ref> This may also apply to choline.{{Citation needed|date=January 2020}} Certain [[mutation]]s that disturb choline metabolism increase the prevalence of NTDs in newborns, but the role of dietary choline deficiency remains unclear, {{as of|2015|lc=y|post=.}}<ref name=lpi/>

===Cardiovascular diseases and cancer===

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.<ref name=eu/> However, [[observational studies]] of free populations have not convincingly shown an association between low choline intake and cardiovascular diseases or most cancers.<ref name=lpi/><ref name=eu/> Studies on [[prostate cancer]] have been contradictory.<ref>{{cite journal | vauthors = Richman EL, Kenfield SA, Stampfer MJ, Giovannucci EL, Zeisel SH, Willett WC, Chan JM | title = Choline intake and risk of lethal prostate cancer: incidence and survival | journal = The American Journal of Clinical Nutrition | volume = 96 | issue = 4 | pages = 855–63 | date = October 2012 | pmid = 22952174 | pmc = 3441112 | doi = 10.3945/ajcn.112.039784 }}</ref><ref>{{cite journal | vauthors = Han P, Bidulescu A, Barber JR, Zeisel SH, Joshu CE, Prizment AE, Vitolins MZ, Platz EA | display-authors = 6 | title = Dietary choline and betaine intakes and risk of total and lethal prostate cancer in the Atherosclerosis Risk in Communities (ARIC) Study | journal = Cancer Causes & Control | volume = 30 | issue = 4 | pages = 343–354 | date = April 2019 | pmid = 30825046 | pmc = 6553878 | doi = 10.1007/s10552-019-01148-4 }}</ref>

===Cognition===

Studies observing the effect between higher choline intake and [[cognition]] have been conducted in human adults, with contradictory results.<ref name=lpi/><ref>{{cite journal|vauthors=Wiedeman AM, Barr SI, Green TJ, Xu Z, Innis SM, Kitts DD|date=October 2018|title=Dietary Choline Intake: Current State of Knowledge Across the Life Cycle|journal=Nutrients|volume=10|issue=10|pages=1513|doi=10.3390/nu10101513|pmc=6213596|pmid=30332744|doi-access=free}}</ref> Similar studies on human infants and children have been contradictory and also limited.<ref name=lpi/>

==Perinatal development==

{{more citations needed section|date=December 2016}}

Both pregnancy and lactation increase demand for choline dramatically. This demand may be met by upregulation of [[Phosphatidyl ethanolamine methyltransferase|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.<ref name="Zeisel, SH. Choline 2006">{{cite journal | vauthors = Zeisel SH | title = Choline: critical role during fetal development and dietary requirements in adults | journal = Annual Review of Nutrition | volume = 26 | pages = 229–50 | year = 2006 | pmid = 16848706 | pmc = 2441939 | doi = 10.1146/annurev.nutr.26.061505.111156 }}</ref>

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.<ref name="Zeisel, SH. Choline 2006"/>

===Functions in the fetus===

Choline is in high demand during pregnancy as a substrate for building [[cellular membrane]]s (rapid fetal and mother tissue expansion), increased need for one-carbon [[Moiety (chemistry)|moieties]] (a substrate for methylation of DNA and other functions), raising choline stores in fetal and placental tissues, and for increased production of lipoproteins (proteins containing "fat" portions).<ref>{{cite book | title = Institute of Medicine, Food and Nutrition Board. Dietary reference intakes for Thiamine, Riboflavin, Niacin, Vitamin B₆, Folate, Vitamin B₁₂, Pantothenic Acid, Biotin and Choline. | location = Washington, DC | publisher = National Academies Press | date = 1998 }}</ref><ref>{{cite book | vauthors = Allen LH | chapter = Pregnancy and lactation | veditors = Bowman BA, Russle RM | title = Present Knowledge in Nutrition | location = Washington DC | publisher = ILSI Press | date = 2006 | pages = 529–543 }}</ref><ref>{{cite journal | vauthors = King JC | title = Physiology of pregnancy and nutrient metabolism | journal = The American Journal of Clinical Nutrition | volume = 71 | issue = 5 Suppl | pages = 1218S–25S | date = May 2000 | pmid = 10799394 | doi = 10.1093/ajcn/71.5.1218s | doi-access = free }}</ref> In particular, there is interest in the impact of choline consumption on the brain. This stems from choline's use as a material for making cellular membranes (particularly in making phosphatidylcholine). Human brain growth is most rapid during the [[third trimester]] of pregnancy and continues to be rapid to approximately five years of age.<ref>{{cite journal | vauthors = Morgane PJ, Mokler DJ, Galler JR | title = Effects of prenatal protein malnutrition on the hippocampal formation | journal = Neuroscience and Biobehavioral Reviews | volume = 26 | issue = 4 | pages = 471–83 | date = June 2002 | pmid = 12204193 | doi = 10.1016/s0149-7634(02)00012-x | s2cid = 7051841 }}</ref> During this time, the demand is high for sphingomyelin, which is made from phosphatidylcholine (and thus from choline), because this material is used to [[Myelinated nerve fibers|myelinate]] (insulate) [[nerve fiber]]s.<ref>{{cite journal | vauthors = Oshida K, Shimizu T, Takase M, Tamura Y, Shimizu T, Yamashiro Y | title = Effects of dietary sphingomyelin on central nervous system myelination in developing rats | journal = Pediatric Research | volume = 53 | issue = 4 | pages = 589–93 | date = April 2003 | pmid = 12612207 | doi = 10.1203/01.pdr.0000054654.73826.ac | doi-access = free }}</ref> Choline is also in demand for the production of the neurotransmitter acetylcholine, which can influence the structure and organization of brain regions, [[neurogenesis]], myelination, and [[synapse]] formation. Acetylcholine is even present in the placenta and may help control [[cell proliferation]] and [[Cell differentiation|differentiation]] (increases in cell number and changes of multiuse cells into dedicated cellular functions) and [[parturition]].<ref>{{cite journal | vauthors = Sastry BV | title = Human placental cholinergic system | journal = Biochemical Pharmacology | volume = 53 | issue = 11 | pages = 1577–86 | date = June 1997 | pmid = 9264309 | doi = 10.1016/s0006-2952(97)00017-8 }}</ref><ref>{{cite journal | vauthors = Sastry BV, Sadavongvivad C | title = Cholinergic systems in non-nervous tissues | journal = Pharmacological Reviews | volume = 30 | issue = 1 | pages = 65–132 | date = March 1978 | pmid = 377313 }}</ref>

Choline uptake into the brain is controlled by a low-affinity transporter located at the blood–brain barrier.<ref>{{cite journal | vauthors = Lockman PR, Allen DD | title = The transport of choline | journal = Drug Development and Industrial Pharmacy | volume = 28 | issue = 7 | pages = 749–71 | date = August 2002 | pmid = 12236062 | doi = 10.1081/DDC-120005622 | s2cid = 34402785 }}</ref> Transport occurs when arterial blood plasma choline concentrations increase above 14&nbsp;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.<ref>{{cite journal | vauthors = Caudill MA | title = Pre- and postnatal health: evidence of increased choline needs | journal = Journal of the American Dietetic Association | volume = 110 | issue = 8 | pages = 1198–206 | date = August 2010 | pmid = 20656095 | doi = 10.1016/j.jada.2010.05.009 }}</ref>

==Uses==

Choline [[chloride]] and choline [[bitartrate]] are used in [[dietary supplement]]s. Bitartrate is used more often due to its lower hygroscopicity.<ref name=ze/> Certain choline salts are used to supplement chicken, turkey and some other [[animal feed]]s. Some salts are also used as industrial chemicals: for example, in [[photolithography]] to remove [[photoresist]].<ref name=":2" /> [[Choline theophyllinate]] and choline [[salicylate]] are used as medicines,<ref name=":2" /><ref>{{Cite book|title=Community pharmacy: symptoms, diagnosis, and treatment|vauthors=Rutter P|publisher=Elsevier|year=2017|isbn=9780702069970|edition=4th|pages=156}}</ref> as well as [[structural analog]]s, like [[methacholine]] and [[carbachol]].<ref name="KOECT">{{cite book | chapter = C2-Chlorocarbons to Combustion Technology |title=Kirk-Othmer encyclopedia of chemical technology | veditors = Howe-Grant M, Kirk RE, Othmer DF |publisher=John Wiley & Sons |year=2000 |isbn=9780471484943 |edition=4th |volume=6 |pages=100–102 |display-authors=etal }}</ref> [[Radiolabeled]] cholines, like [[carbon-11-choline|¹¹C-choline]], are used in [[medical imaging]].<ref>{{cite journal | vauthors = Guo Y, Wang L, Hu J, Feng D, Xu L | title = Diagnostic performance of choline PET/CT for the detection of bone metastasis in prostate cancer: A systematic review and meta-analysis | journal = PLOS ONE | volume = 13 | issue = 9 | pages = e0203400 | date = 2018 | pmid = 30192819 | pmc = 6128558 | doi = 10.1371/journal.pone.0203400 | bibcode = 2018PLoSO..1303400G | doi-access = free }}</ref> Other commercially used salts include tricholine [[citrate]] and choline [[bicarbonate]].<ref name=:2/>

==Antagonists and inhibitors==

Hundreds of choline [[Receptor antagonist|antagonists]] and [[enzyme inhibitor]]s have been developed for research purposes. [[Aminomethyl propanol|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|''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.<ref name=ze/>

The [[cholinergic]] hypothesis of [[dementia]] has not only lead to medicinal [[acetylcholinesterase inhibitor]]s, but also to a variety of [[acetylcholine inhibitor]]s. 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.<ref name=ze/>

==History==

===Discovery===

In 1849, [[Adolph Strecker]] was the first to isolate choline from pig bile.<ref>{{cite journal |vauthors=Strecker A |date=1849 |title=Beobachtungen über die galle verschiedener thiere |journal=Justus Liebigs Ann Chem |language=de |volume=70 |issue=2 |pages=149–197 |doi=10.1002/jlac.18490700203 |url=https://zenodo.org/record/1427022 }}</ref><ref name="Sebrell_1971">{{cite book |title=The vitamins |vauthors=Sebrell WH, Harris RS, Alam SQ |publisher=Academic Press |year=1971 |isbn=9780126337631 |edition=2nd |volume=3 |pages=4, 12 |doi=10.1016/B978-0-12-633763-1.50007-5 }}</ref> In 1852, L. Babo and M. Hirschbrunn extracted choline from [[white mustard]] seeds and named it ''sinkaline''.<ref name="Sebrell_1971" /> 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.<ref name="Strecker_1862">{{Cite journal|vauthors=Strecker A|date=1862|title=Üeber einige neue bestandtheile der schweinegalle|journal=Justus Liebigs Ann Chem|language=de|volume=123|issue=3|pages=353–360|doi=10.1002/jlac.18621230310 |url=https://zenodo.org/record/1427185}}</ref><ref name=his>{{cite journal | vauthors = Zeisel SH | title = A brief history of choline | journal = Annals of Nutrition & Metabolism | volume = 61 | issue = 3 | pages = 254–8 | date = 2012 | pmid = 23183298 | pmc = 4422379 | doi = 10.1159/000343120 }}</ref> In 1850, [[Theodore Nicolas Gobley]] extracted from the brains and [[roe]] of [[carp]]s a substance he named ''lecithin'' after the Greek word for egg [[yolk]], {{transliteration|el|lekithos}}, showing in 1874 that it was a mixture of [[phosphatidylcholines]].<ref>{{Cite journal|vauthors=Gobley T|date=1874|title=Sur la lécithine et la cérébrine|url=https://archive.org/details/journaldepharma26parigoog|journal=J Pharm Chim|language=fr|volume=19|issue=4|pages=[https://archive.org/details/journaldepharma26parigoog/page/n352 346]–354}}</ref><ref>{{Cite journal|vauthors=Sourkes TL|date=2004|title=The discovery of lecithin, the first phospholipid|url=http://acshist.scs.illinois.edu/bulletin_open_access/v29-1/v29-1%20p9-15.pdf|journal=Bull Hist Chem|volume=29|issue=1|pages=9–15|archive-url=https://web.archive.org/web/20190413044150/http://acshist.scs.illinois.edu/bulletin_open_access/v29-1/v29-1%20p9-15.pdf|archive-date=2019-04-13|url-status=live}}</ref>

In 1865, [[Oscar Liebreich]] isolated "''neurine''" from animal brains.<ref>{{Cite journal|vauthors=Liebreich O|date=1865|title=Üeber die chemische beschaffenheit der gehirnsubstanz|journal=Justus Liebigs Ann Chem|language=de|volume=134|issue=1|pages=29–44|doi=10.1002/jlac.18651340107 |s2cid=97165871 |url=https://zenodo.org/record/1769614}}</ref><ref name="his" /> The [[structural formula]]s of acetylcholine and Liebreich's "neurine" were resolved by [[Adolf von Baeyer]] in 1867.<ref name="b">{{Cite journal|vauthors=Baeyer A|date=1867|title=I. Üeber das neurin|journal=Justus Liebigs Ann Chem|language=de|volume=142|issue=3|pages=322–326|doi=10.1002/jlac.18671420311|url=https://zenodo.org/record/2483316}}</ref><ref name="Sebrell_1971"/> 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.<ref>{{cite journal|vauthors=Dybkowsky W|trans-title=On the identity of choline & neurin|date=1867|title=Üeber die identität des cholins und des neurins|journal=J Prakt Chem|language=de|volume=100|issue=1|pages=153–164|doi=10.1002/prac.18671000126 |url=https://zenodo.org/record/1850615}}</ref><ref>{{cite journal |vauthors=Claus A, Keesé C |date=1867 |title=Üeber neurin und sinkalin |journal=J Prakt Chem |language=de |volume=102 |issue=1 |pages=24–27 |doi=10.1002/prac.18671020104 |url=https://zenodo.org/record/2464361 }}</ref><ref name="Sebrell_1971" /> The compound now known as [[neurine]] is unrelated to choline.<ref name="his" />

===Discovery as a nutrient===

In the early 1930s, [[Charles Best (medical scientist)|Charles Best]] and colleagues noted that fatty liver in rats on a special diet and [[diabetic]] dogs could be prevented by feeding them lecithin,<ref name=his/> proving in 1932 that choline in lecithin was solely responsible for this preventive effect.<ref>{{cite journal | vauthors = Best CH, Hershey JM, Huntsman ME | title = The effect of lecithine on fat deposition in the liver of the normal rat | journal = The Journal of Physiology | volume = 75 | issue = 1 | pages = 56–66 | date = May 1932 | pmid = 16994301 | pmc = 1394511 | doi = 10.1113/jphysiol.1932.sp002875 }}</ref> In 1998, the US National Academy of Medicine reported their first recommendations for choline in the human diet.<ref>{{Cite book|title=Institute of Medicine (US) Standing Committee on the scientific evaluation of dietary reference intakes and its panel on folate, other B. vitamins, and choline|chapter=Choline |url=https://www.ncbi.nlm.nih.gov/books/NBK114308/|publisher=National Academies Press (US)|year=1998|pages=xi, 402–413|isbn=9780309064118}}</ref>

== References ==

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{{Reflist}}

{{Dietary supplements}}

{{Acetylcholine receptor modulators}}

{{Acetylcholine metabolism and transport modulators}}

{{Authority control}}

[[Category:Essential nutrients]]

[[Category:Primary alcohols]]

[[Category:Cholinergics]]

[[Category:Quaternary ammonium compounds]]

[[Category:Dietary supplements]]