1. Quasi-vitamins: Choline
Domina Petric, MD

2. Chemical nature
Choline is the trivial designation for the compound 2-hydroxy-N,N,N-trimethylethanaminium.
It is freely soluble in water and ethanol, but insoluble in organic solvents.
It is a strong base and decomposes in alkaline solution with the release of trimethylamine.
The prominent feature of its chemical structure is its triplet of methyl groups, which enables it to serve as a methyl donor.
November 14, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

3. Distribution in foods All natural fats contain some choline.
Choline occurs naturally mostly in the form of phosphatidylcholine (lecithin).
Lecithin is used as an ingredient or additive in many foods and food supplements because it is a good emulsifying agent.
November 14, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

4. Distribution in foods
Some dietary choline (<10%) is present as the free base and sphingomyelin.
Choline is added (as choline chloride and choline bitartrate) to infant formulas as a means of fortification .
November 14, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

5. Meats Meat Choline mg/g Beef brain 410 Beef liver 630 Beef kidney 333
Ham
120
Trout 84
November 14, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

6. Cereals Cereals Choline mg/g Barley 139 Oats 151 Polished rice 126
Wheat germ
423
November 14, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

7. Vegetables Vegetables Choline mg/g Asparagus 128 Cabbage 46 Carrots 10
Cauliflower 78
Lettuce 18
Soybeans
237
Peanuts
145
November 14, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

8. Diary and egg products Dairy and egg products Choline mg/g Milk 10
Egg yolk
1713
November 14, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

9. Absorption
Choline is released from phosphatidylcholine by hydrolysis in the intestinal lumen.
This is accomplished enzymatically through the action of phospholipases produced by the pancreas (phospholipase A2, which cleaves the β-ester bond) and the intestinal mucosa (phospholipases A1 and B, both of which cleave the α-ester bond to yield glycerylphosphorylcholine).
November 14, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

10. Absorption
The mucosal enzymes are much less efficient than the pancreatic enzyme.
Most of the phosphatidylcholine that is ingested is absorbed as lysolecithin (deacylated only in the α position), which is reacylated to yield phosphatidylcholine.
November 14, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

11. Absorption
This reaction involves the dismutation of two molecules of lysolecithin to yield one molecule of glycerylphosphorylcholine and one molecule of phosphatidylcholine.
Analogous reactions occur with sphingomyelin, which, unlike phosphatidylcholine, is not degraded in the intestinal lumen, but is taken up intact by the intestinal mucosa.
November 14, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

12. The remaining portion is absorbed intact.
Absorption
When free choline or one of its salts is consumed, a large amount (nearly two-thirds) is catabolized by intestinal microorganisms to the end product trimethylamine, much of which is absorbed and excreted in the urine.
The remaining portion is absorbed intact.
Phosphatidylcholine is not subject to such extensive microbial metabolism and, therefore, produces less urinary trimethylamine.
November 14, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

13. Absorption
Choline is absorbed in the upper portion of the small intestine by a saturable, carrier-mediated process involving a carrier localized in the brush border, and efficient at low lumenal concentrations (<4 mM).
At high lumenal concentrations, it is also absorbed by passive diffusion.
November 14, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

14. Uptake and transport
Recently absorbed choline is transported into the lymphatic circulation primarily in the form of phosphatidylcholine bound to chylomicra, which are subject to clearance to the lipoproteins that circulate to the peripheral tissues.
Choline is transported to the tissues predominantly as phospholipids associated with the plasma lipoproteins.
November 14, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

15. Choline is taken up into cells by three transport systems:
● By a high-affinity, Na+-dependent transporter (CHT1) that provides choline for the synthesis of acetylcholine in cholinergic neurons. ● By low-affinity, Na+-independent transporters of the family of organic cation transporters (OCTs). ● By passive diffusion.
November 14, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

16. Uptake and transport
Choline is present in all tissues as an essential component of phospholipids in membranes of all types.
It is stored in the greatest concentrations in the essential organs (brain, liver, kidney) in the forms of phosphatidylcholine and sphingomyelins.
Placental tissues are unique in that they accumulate large amounts of acetylcholine, presumably to meet fetal needs, which is otherwise present only in the parasympathetic nervous system.
November 14, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

17. Biosynthesis
There are three means of phosphatidylcholine biosynthesis:
methylation of ethanolamine
reaction of cytidine diphosphate
phospholipid base exchange (substitution of choline for serine, ethanolamine or inositol in endogenous phospholipids)
Of these, only the methylation pathway involves the de novo synthesis of choline.
November 14, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

18. Biosynthesis
Most animal species can synthesize choline, as phosphatidylcholine, by the sequential methylation of phosphatidylethanolamine by phosphatidylethanolamine N-methyltransferase.
This activity is due to two enzymes:
cell inner membrane enzyme adds the first methyl group
cell outer membrane enzyme adds the second and third methyl groups
November 14, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

19. Each enzyme uses S-adenosylmethionine as the methyl donor.
Biosynthesis
Each enzyme uses S-adenosylmethionine as the methyl donor.
November 14, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

20. Metabolism
Choline is released in free form in the tissues by the actions of phospholipase C.
Phospholipase C cleaves the circulating form (phosphatidylcholine) to yield a diglyceride and phosphorylcholine.
Phosphorylcholine is converted to free choline by alkaline phosphatase.
November 14, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

21. Metabolism
Peripheral tissues contain phospholipase B activity and can therefore produce glycerylphosphorylcholine from the circulating form of the vitamin.
That product can then be cleaved by glycerylphosphorylcholine diesterase to yield free choline.
The brain contains phospholipase D, which cleaves free choline directly from the circulating form (also yielding glycerylphosphate).
November 14, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

22. Metabolism
Free choline can be oxidized by the mitochondrial enzyme choline dehydrogenase to yield betaine aldehyde, which is then converted by the cytosolic enzyme betaine aldehyde dehydrogenase to betaine.
November 14, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

23. Metabolism This dual enzyme system is called choline oxidase.
It is found in liver and kidney, but is notably absent from brain, muscle and blood.
It is induced by dietary choline.
Choline is oxidized to betaine at a rate that is an order of magnitude greater than that of its incorporation into phosphorylcholine.
November 14, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

24. Metabolism
Betaine cannot be reduced back, but it can donate its methyl groups to homocysteine to produce dimethylglycine and methionine by the action of the enzyme betaine:homocysteine methyltransferase.
While the choline oxidase pathway removes free choline from the body, it also serves as a source of labile methyl groups.
November 14, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

25. Metabolism
Free choline is phosphorylated by the cytosolic enzyme choline phosphotransferase (also called choline kinase), using ATP as the phosphate donor.
This step occurs in many tissues and constitutes the first step in the generation of cytidine diphosphorylcholine (CDP-choline), which combines with diacylglycerol (by the action of phosphatidylcholine glyceride transferase) in the synthesis of phosphatidylcholine.
November 14, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

26. Metabolism
Only a small fraction of choline is acetylated, but that amount provides the important neurotransmitter acetylcholine.
This step involves the reaction of choline with acetyl-CoA and is catalyzed by an enzyme choline acetyltransferase localized in cholinergic nerve terminals, as well as in certain other non-nervous tissues (like placenta).
November 14, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

27. Metabolism
Because brain choline acetyltransferase does not appear to be saturated with either substrate, it is likely that the availability of choline (as well as that of acetyl-CoA) may determine the rate of synthesis of acetylcholine.
November 14, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

28. Metabolic functions
November 14, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

29. As phosphatidylcholine
Structural element of biological membranes!
Precursor to ceramide, the basic structure of sphingolipids, which play roles in transmembrane signal transduction.
Promoter of lipid transport: as a lipotrope.
November 14, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

30. As acetylcholine
It is a neurotransmitter, occurring primarily in the parasympathetic nervous system.
November 14, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

31. As a component of platelet-activating factor
1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine is important in clotting, inflammation, uterine ovum implantation, fetal maturation and induction of labor.
November 14, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

32. As a component of plasmalogen
It has a role in myocardial function.
November 14, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

33. As a source of labile methyl groups
After its irreversible oxidation to betaine, it is a source of labile methyl groups for transmethylation reactions in the formation of methionine from homocysteine, or of creatine from guanidoacetic acid.
November 14, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

34. As a source of labile methyl groups
This function links choline to folate metabolism.
The biosynthesis of methionine by the methylation of homocysteine by methyltetrahydrofolate cannot meet all of the intracellular demands for S-adenosylmethionine.
Choline constitutes an important dietary source of labile methyl groups for homocysteine transmethylation.
November 14, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

35. Role in carcinogenesis
Choline deficiency in animal models has been found to increase the incidence of spontaneous hepatocarcinomas in the absence of any known carcinogen and to enhance hepatocarcinogenesis induced chemically.
November 14, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

36. Health effects
November 14, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

37. Health effects
The intake of choline can affect the concentrations of the neurotransmitter acetylcholine in the brain.
Choline loading may be beneficial to patients with diseases involving deficiencies of cholinergic neurotransmission.
November 14, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

38. Health effects
Large doses (multiple-gram quantities) of choline have been used to increase brain choline concentrations above normal levels, thereby stimulating the synthesis of acetylcholine in nerve terminals.
Such supplementation has been found to help in the treatment of tardive dyskinesia (inadequate neurotransmission at striatal cholinergic interneurons).
November 14, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

39. Health effects
Choline supplements have also been used with some success to improve free memory in subjects without dementia and diminish short-term memory losses associated with Alzheimer’s disease.
November 14, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

40. Health effects
It has been suggested that auto-cannibalism of membrane phosphatidylcholine may be an underlying defect in Alzheimer´s disease.
November 14, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

41. Phosphatidylcholine has been reported to reduce manic episodes.
Health effects
Phosphatidylcholine has been reported to reduce manic episodes.
Such treatment has been found to exacerbate depression among tardive dyskinesia patients.
November 14, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

42. Toxicity
November 14, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

43. Toxicity The toxicity of choline appears to be very low.
Deleterious effects have been reported for the high dose of salt choline chloride: growth depression, impaired utilization of vitamin B6 and increased mortality.
November 14, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

44. Literature
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc
November 14, 2018