Choline chemical properties, significance, distribution in foods, absorption, metabolism, metabolic functions, choline deficiency and toxicity

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.
April 24, 2018
Combs GF. The Vitamins. Fundamental Aspects in
Nutrition and Health. Elsevier Inc. 2008.
2

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.
April 24, 2018
Combs GF. The Vitamins. Fundamental Aspects in
Nutrition and Health. Elsevier Inc. 2008.
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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 .
April 24, 2018
Combs GF. The Vitamins. Fundamental Aspects in
Nutrition and Health. Elsevier Inc. 2008.
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5. Meats
Meat Choline mg/g
Beef brain 410
Beef liver 630
Beef kidney 333
Ham 120
Trout 84
April 24, 2018
Combs GF. The Vitamins. Fundamental Aspects in
Nutrition and Health. Elsevier Inc. 2008.
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6. Cereals
Cereals Choline mg/g
Barley 139
Oats 151
Polished rice 126
Wheat germ 423
April 24, 2018
Combs GF. The Vitamins. Fundamental Aspects in
Nutrition and Health. Elsevier Inc. 2008.
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7. Vegetables
Vegetables Choline mg/g
Asparagus 128
Cabbage 46
Carrots 10
Cauliflower 78
Lettuce 18
Soybeans 237
Peanuts 145
April 24, 2018
Combs GF. The Vitamins. Fundamental Aspects in
Nutrition and Health. Elsevier Inc. 2008.
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8. Diary and egg products
Dairy and egg
products
Choline mg/g
Milk 10
Egg yolk 1713
April 24, 2018
Combs GF. The Vitamins. Fundamental Aspects in
Nutrition and Health. Elsevier Inc. 2008.
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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).
April 24, 2018
Combs GF. The Vitamins. Fundamental Aspects in
Nutrition and Health. Elsevier Inc. 2008.
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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.
April 24, 2018
Combs GF. The Vitamins. Fundamental Aspects in
Nutrition and Health. Elsevier Inc. 2008.
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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.
April 24, 2018
Combs GF. The Vitamins. Fundamental Aspects in
Nutrition and Health. Elsevier Inc. 2008.
11

12. 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.
April 24, 2018
Combs GF. The Vitamins. Fundamental Aspects in
Nutrition and Health. Elsevier Inc. 2008.
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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.
April 24, 2018
Combs GF. The Vitamins. Fundamental Aspects in
Nutrition and Health. Elsevier Inc. 2008.
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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.
April 24, 2018
Combs GF. The Vitamins. Fundamental Aspects in
Nutrition and Health. Elsevier Inc. 2008.
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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.
April 24, 2018
Combs GF. The Vitamins. Fundamental Aspects in
Nutrition and Health. Elsevier Inc. 2008.
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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.
April 24, 2018
Combs GF. The Vitamins. Fundamental Aspects in
Nutrition and Health. Elsevier Inc. 2008.
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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.
April 24, 2018
Combs GF. The Vitamins. Fundamental Aspects in
Nutrition and Health. Elsevier Inc. 2008.
17

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
April 24, 2018
Combs GF. The Vitamins. Fundamental Aspects in
Nutrition and Health. Elsevier Inc. 2008.
18

19. Biosynthesis
Each enzyme uses
S-adenosylmethionine
as the methyl donor.
April 24, 2018
Combs GF. The Vitamins. Fundamental Aspects in
Nutrition and Health. Elsevier Inc. 2008.
19

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.
April 24, 2018
Combs GF. The Vitamins. Fundamental Aspects in
Nutrition and Health. Elsevier Inc. 2008.
20

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).
April 24, 2018
Combs GF. The Vitamins. Fundamental Aspects in
Nutrition and Health. Elsevier Inc. 2008.
21

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.
April 24, 2018
Combs GF. The Vitamins. Fundamental Aspects in
Nutrition and Health. Elsevier Inc. 2008.
22

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.
April 24, 2018
Combs GF. The Vitamins. Fundamental Aspects in
Nutrition and Health. Elsevier Inc. 2008.
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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.
April 24, 2018
Combs GF. The Vitamins. Fundamental Aspects in
Nutrition and Health. Elsevier Inc. 2008.
24

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.
April 24, 2018
Combs GF. The Vitamins. Fundamental Aspects in
Nutrition and Health. Elsevier Inc. 2008.
25

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).
April 24, 2018
Combs GF. The Vitamins. Fundamental Aspects in
Nutrition and Health. Elsevier Inc. 2008.
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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.
April 24, 2018
Combs GF. The Vitamins. Fundamental Aspects in
Nutrition and Health. Elsevier Inc. 2008.
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28. Metabolic functions
April 24, 2018
Combs GF. The Vitamins. Fundamental Aspects in
Nutrition and Health. Elsevier Inc. 2008.
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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.
April 24, 2018
Combs GF. The Vitamins. Fundamental Aspects in
Nutrition and Health. Elsevier Inc. 2008.
29

30. As acetylcholine
It is a neurotransmitter,
occurring primarily in
the parasympathetic
nervous system.
April 24, 2018
Combs GF. The Vitamins. Fundamental Aspects in
Nutrition and Health. Elsevier Inc. 2008.
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31. As a component of platelet-activating factor
April 24, 2018
Combs GF. The Vitamins. Fundamental Aspects in
Nutrition and Health. Elsevier Inc. 2008.
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32. As a component of plasmalogen
It has a
role in
myocardial
function.
April 24, 2018
Combs GF. The Vitamins. Fundamental Aspects in
Nutrition and Health. Elsevier Inc. 2008.
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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.
April 24, 2018
Combs GF. The Vitamins. Fundamental Aspects in
Nutrition and Health. Elsevier Inc. 2008.
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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
5-methyltetrahydrofolate cannot meet all of the
intracellular demands for
S-adenosylmethionine.
Choline constitutes an important
dietary source of labile methyl groups
for homocysteine transmethylation.
April 24, 2018
Combs GF. The Vitamins. Fundamental Aspects in
Nutrition and Health. Elsevier Inc. 2008.
34

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.
April 24, 2018
Combs GF. The Vitamins. Fundamental Aspects in
Nutrition and Health. Elsevier Inc. 2008.
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36. Health effects
April 24, 2018
Combs GF. The Vitamins. Fundamental Aspects in
Nutrition and Health. Elsevier Inc. 2008.
36

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.
April 24, 2018
Combs GF. The Vitamins. Fundamental Aspects in
Nutrition and Health. Elsevier Inc. 2008.
37

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).
April 24, 2018
Combs GF. The Vitamins. Fundamental Aspects in
Nutrition and Health. Elsevier Inc. 2008.
38

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.
April 24, 2018
Combs GF. The Vitamins. Fundamental Aspects in
Nutrition and Health. Elsevier Inc. 2008.
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40. Health effects
April 24, 2018
Combs GF. The Vitamins. Fundamental Aspects in
Nutrition and Health. Elsevier Inc. 2008.
40

41. Health effects
Phosphatidylcholine has
been reported to reduce
manic episodes.
Such treatment has been
found to exacerbate
depression among tardive
dyskinesia patients.
April 24, 2018
Combs GF. The Vitamins. Fundamental Aspects in
Nutrition and Health. Elsevier Inc. 2008.
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42. Toxicity
April 24, 2018
Combs GF. The Vitamins. Fundamental Aspects in
Nutrition and Health. Elsevier Inc. 2008.
42

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.
April 24, 2018
Combs GF. The Vitamins. Fundamental Aspects in
Nutrition and Health. Elsevier Inc. 2008.
43

44. Literature
• Combs GF. The Vitamins. Fundamental Aspects in
Nutrition and Health. Elsevier Inc. 2008.
April 24, 2018 44