The major pathway for phosphatidylcholine
synthesis in the body utilizes preformed or dietary choline. In an
alternative pathway for phosphatidylcholine biosynthesis,
phosphatidylcholine is sequentially methylated to form phosphatidylcholine,
using S-adenosylmethionine as the methyl donor. This is probably the only
pathway for de novo synthesis of choline in the body. However,
de novo synthesis does not appear adequate to meet the demand for the
nutrient.
ACTIONS AND
PHARMACOLOGY
ACTIONS
Choline is a precursor for phosphatidylcholine,
sphingomyelin, acetylcholine and the methyl donor betaine. Thus, choline
is important for normal cellular membrane composition and repair, normal
brain function and normal cardiovascular function.
Choline
is important for normal cellular membrane composition and repair, normal
brain function and
normal cardiovascular function
MECHANISM OF
ACTION
Choline is involved in several basic biological
processes. Choline is a major part of the polar head group of
phosphatidylcholine. Phosphatidylcholine's role in the maintenance of cell
membrane integrity is vital to all of the basic biological processes:
information flow, intracellular communication and bioenergetics.
Inadequate choline intake would negatively affect all these processes.
Choline is also a major part of another membrane phospholipid,
sphingomyelin, also important for the maintenance of cell structure and
function. It is noteworthy and not surprising that choline deficiency in
cell culture causes apoptosis or programmed cell death. This appears to be
due to abnormalities in cell membrane phosphatidylcholine content and an
increase in ceramide, a precursor, as well as a metabolite, of
sphingomyelin. Ceramide accumulation, which is caused by choline
deficiency, appears to activate a caspase, a type of enzyme that mediates
apoptosis.
Evidence is mounting that an elevated
homocysteine level is a significant risk factor for atherosclerosis, as
well as other cardiovascular and neurological disorders. Betaine or
trimethylglycine is derived from choline via an oxidation reaction.
Betaine is one of the factors that maintains low levels of homocysteine by
resynthesizing L-methionine from homocysteine.
Acetylcholine is one of the major
neurotransmitters and requires choline for its synthesis. Adequate
acetylcholine levels in the brain are believed to be protective against
certain types of dementia, including Alzheimer's disease. Human studies
are needed to determine whether dietary choline might be useful in the
prevention of dementia.
The mechanism of the carcinogenic actions of
choline deficiency are not known.
Adequate acetylcholine
levels in the brain are believed to be protective against certain types of
dementia,
including Alzheimer's disease.
PHARMACOKINETICS
Choline is absorbed from the small intestine by
means of transporter proteins in the intestinal cells. Some choline is
metabolized in the gut to betaine (trimethylglycine) and trimethylamine,
which are also absorbed by the gut. Choline, as well as betaine and
trimethylamine, are transported to the liver via portal circulation. All
tissues accumulate choline by diffusion and mediated transport.
In the liver, choline participates in various
metabolic reactions, including the formation of CDP-choline, which
combines with diacylglycerol to form phosphatidylcholine. Through
oxidation, it forms the methyl donor betaine. Trimethylamine, a choline
metabolite, is oxidized to trimethylamine oxide in the liver. Choline is
transported across the blood-brain barrier by a specific carrier
mechanism. Within the brain and other nervous tissue, choline is converted
to acetylcholine by the enzyme choline acetyltransferase. Only a small
fraction of dietary choline goes to form acetylcholine. The kidney also
accumulates choline. Some appears in the urine unchanged but most is
oxidized to form betaine.
INDICATIONS AND
USAGE
Increased choline intake has recently been
recommended by the Food and Nutrition Board of the National Academy of
Sciences for pregnant and nursing women to help ensure normal fetal brain
development. And, like phosphatidylcholine (see Phosphatidylcholine),
choline may be helpful in some liver diseases, manic conditions, cognitive
disorders, tardive dyskinesia and, possibly, some cancers.
RESEARCH SUMMARY
There is some evidence, derived from animal
studies, that choline, if present in adequate amounts during pregnancy and
breast feeding, can help ensure healthy fetal brain development. These
studies further suggest that adequate prenatal choline can have
long-lasting positive effects on cognitive function, including memory.
In a series of studies, the diets of pregnant
rats have been supplemented with varying amounts of choline for variable
periods of time during gestation. Supplementation, especially during the
second half of pregnancy, has been strongly associated with positive
cognitive effects (which are not seen in control animals receiving little
or no choline).
Tested as adults, rats that had received
approximately three times control amounts of choline during gestation were
significantly superior in tasks that assess attention and spatial and
temporal memory. Offspring of mothers that received no choline during
pregnancy had attention and memory task impairment. And, even though both
control and experimental animals were given the same standardized normal
diet after birth, those whose mothers got higher levels of choline during
pregnancy continued to exhibit significant cognitive superiority over
controls throughout life. "Thus," one of the researchers concluded,
"prenatal supplementation with choline prevented the normally observed
memory decline of old age."
These significant studies are buttressed by
neuroanatomical, neurophysiological and neurochemical studies that have
similarly shown that choline has positive, long-lasting effects on
prenatal brain development at the cellular level. Some of these studies
have produced direct evidence that choline supplementation stimulates cell
division in the embryonic brain, while choline deficiency increases
apoptosis in areas of the brain, principally the hippocampus and septum,
associated with memory processing. It has been hypothesized that choline
supplementation during gestation may exert its apparent long-term effects
through cellular and synaptic modifications that permanently increase
memory-processing capacity.
Human studies have yet to be conducted on
choline's effects on the fetus, but one researcher concludes that there is
hope that "optimal dietary choline early in life may improve human
cognitive development and slow cognitive declines associated with aging."
The Food and Nutrition Board of the National
Academy of Sciences is impressed enough with research to date that it has
recently recommended that pregnant and nursing women increase their intake
of choline. The board recommends 425 milligrams of choline daily for women
who are not pregnant, 450 milligrams daily for pregnant women and 550
milligrams daily for nursing women.
For information about other research related to
choline, see Phosphatidylcholine.
CONTRAINDICATIONS, PRECAUTIONS, ADVERSE REACTIONS
CONTRAINDICATIONS
No contraindications are reported.
PRECAUTIONS
Trimethylaminuria or fish-odor syndrome:
Trimethylaminuria is a rare genetic metabolic disorder occurring in oil to
0.1 to 1% of the population. It is due to deficiency of the enzyme
trimethylamine-N-oxide synthetase, which converts trimethylamine to
trimethylamine-N-oxide. Trimethylamine, which is produced from choline, is
excreted from the body via the urine, sweat, breath and other bodily
secretions. It has a nauseating, rotten-fish-smelling odor. Trimethylamine-N-oxide,
the metabolite of trimethylamine, is non-odorous. Those with primary
genetic trimethyluria (the inherited enzyme deficiency) should restrict
intake of choline. Also, those with certain types of liver disease caused
by any of the hepatitis viruses or from other etiologies may develop fishy
body odor when taking supplemental choline. Choline intake should be
restricted in these cases.
ADVERSE
REACTIONS
Choline doses of up to 3 grams daily are
generally well tolerated with occasional reports of nausea, diarrhea and
loose stools. Higher doses have been associated with fishy body
odor—particularly in those with trimethylaminuria (fish-odor syndrome).
Trimethylaminuria may also occur in those with liver damage who are using
high doses of choline. High intakes of choline have been associated with
excessive sweating and hypotension. There are some reports of depression
or increased symptoms of depression in those using high doses of choline
bitartrate.
There are no adequate data demonstrating a
no-observed-adverse-effect level (NOAEL) for excess choline intake. Based
on two clinical studies in humans, a lowest-observed-adverse-effect level
(LOAEL) of 7.5 grams daily has been determined. At 7.5 grams of choline
daily, nausea, diarrhea and a small decrease in blood pressure were
reported in some patients. The upper limit (UL) for adults is 3.5 grams
daily. Individuals that may be at increased risk of side effects with
choline intakes at the UL include those with trimethylaminuria, liver
disease, renal disease, depression and Parkinson's disease.
INTERACTIONS
DRUGS
Methotrexate: Methotrexate may diminish
pools of all choline metabolites. Choline supplementation reverses fatty
liver caused by methotrexate administration in rats.
NUTRITIONAL
SUPPLEMENTS
Choline, via its metabolism to betaine, works in
concert with vitamins B6, B12 and folic acid in the
metabolism of the potentially atherogenic substance homocysteine.
DOSAGE AND
ADMINISTRATION
Typical doses of choline intake range from 300
to 1,200 milligrams daily. The major choline salt forms available are
choline chloride and choline bitartrate.
Phosphatidylcholine is a delivery form of
choline (see Phosphatidylcholine).
Choline is also added to some infant formulas
and to some TPN formulations.
Adequate intakes (AI) of choline have been
established by the Food and Nutrition Board of the Institute of Medicine
of the National Academy of Sciences. The AI for adults is 550 milligrams
daily for men and 425 milligrams daily for women. A summary of Als for
various age groups is as follows:
All of the above values are for the choline
base. Values for choline salts are higher. For example, values for choline
chloride would be 1.4 times as high and for choline bitartrate even
higher. About 13 percent of phosphatidylcholine is choline.
HOW SUPPLIED
Capsules — 350 mg, 648 mg
Powder
Tablets — 250 mg, 500 mg, 648 mg, 650 mg
LITERATURE
Albright CD, Liu R, Berthea TC, et al. Choline
deficiency induces apoptosis in SV 40-immortalized CW SV-1 rat hepatocytes
in culture. FASEB J. 1996; 10:510-516.
Blusztajn JK. Choline, a vital amine. Science.
1998; 281:794-795.
Canty DJ, Zeisel SH. Lecithin and choline in
human health and disease. Nutr Rev. 1994; 52:327-339.
Cohen BM, Renshaw PF, Stoll, AL. Decreased brain
choline uptake in older adults. An in vivo magnetic resonance spectroscopy
study. J Amer Med Ass. 1995; 274:902-907.
Food and Nutrition Board. Institute of Medicine.
Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6,
Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline
(National Academy Press, Washington, DC, 1998).
Pyapili GK, Turner DA, Williams, CL. Prenatal
dietary choline supplementation decreases the threshold for induction of
long-term potentiation in young adult rats. J Neurophysiol. 1998;
79:1790-1796.
Schocke Z, J, Kohlmueller D, Quak E, et al. Mild
trimethylaminuria caused by common variants in FMO3 gene. Lancet.
1997; 354:834-835.
Shelly EP, Shelley WB. The fish odor syndrome.
Trimethyluria. J Amer Med Ass. 1984; 251:253-255.
Wurtman RJ, Hefti F, Melamed E. Precursor
control of neurotransmitter synthesis. Pharmacol Rev. 1981;
32:315-335.
Yen C-L, E Mar, M-H, Zeisel SH. Choline
deficiency-induced apoptosis in PC 12 cells is associated with diminished
membrane phosphatidylcholine and sphingomyelin, accumulation of ceramide
and ciccylglycerol, and activation of a caspace. FASEB J. 1999;
13:135-142.*
*Health statements have
not been evaluated by the FDA. We always recommend you check with your
health care practitioner or physician prior to beginning any new
supplement or diet program, especially if you are on any medication,
nursing, pregnant or have any other existing medical condition.
Therapeutic
Dosage
