Folic Acid (folate) Supplements, Vitamin B12, Effects, Homocysteine

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Fabulous Folate:  Folic Acid in Health - Page 2
by A.S. Gissen - reprinted by permission

Folate and Homocysteine
It is well documented that homocysteinemia metabolism is associated with vascular conditions.  The accumulation of excess quantities of homocysteine accompanies errors of metabolism that decrease the conversion of homocysteine to cystathione or methionine.  These pathways require vitamin B6 or folic acid and vitamin B12 for the proper metabolism of homocysteine.  While the connection between elevated homocysteine concentrations in genetic homocysteinemia was recognized in 1969, the ability of folate deficiency to elevate serum homocysteine has only been generally recognized in the last ten years.

An extraordinarily high serum homocysteine level in humans is a firmly established health problem.  In recent years, however, the possibility that slightly to moderately elevated homocysteine levels among the general population has been increasingly substantiated as a health problem indicator.  This is in spite of the fact that the homocysteine values were within what has been considered the normal range for serum homocysteine concentration.  While extremely high blood homocysteine levels due to rare enzymatic defects in various points of homocysteine metabolic pathways do occur, they are rare and usually result in health problems at a young age.  Moderate elevations, on the other hand, appear to be much more common.
This can result from one of two things; either the result of less severe defects in homocysteine metabolic enzymes, or inadequate amounts of folic acid, and /or vitamin B6, and/or vitamin B12.

Folic acid supplements have been shown to lower the homocysteine concentrations of both homocysteinemic subjects and non-folate-deficient subjects.  Because vitamin B6 and vitamin B12 are also involved in homocysteine metabolism, most recent studies have examined the role of all three nutrients on elevated homocysteine levels.  Compared with a group of healthy controls, subjects with an elevated plasma homocysteine concentration had significantly lower plasma concentrations of vitamin B6, vitamin B12, and folic acid.  In a placebo controlled, follow-up study using the same patients, a daily supplement of 10 mg. vitamin B6, 1 mg. folic acid, and .4 mg vitamin B-12 normalized the elevated plasma homocysteine concentrations within six weeks.  These authors concluded that, "because hyperhomocysteinemia is implicated as a risk factor, appropriate vitamin therapy may be both efficient and cost-effective to control elevated homocysteine concentrations."

A recently published study examining the role of these three vitamins on homocysteine concentrations demonstrated that inadequate folic acid intake is the main determinant of homocysteine-related health problems.  Other recent studies have shown that homocysteine levels rose inversely with folate status.  Interestingly, homocysteine concentrations did not reach a stable low level until folate intake reached approximately 400 micrograms per day or more.  Shockingly, the Recommended Dietary Allowance for folic acid was recently lowered from 400 to 200 micrograms per day.  Additional data has suggested that as much as forty percent of the population is not consuming an adequate amount of folic acid to keep homocysteine concentrations low.  Even in people with elevated homocysteine levels that are unresponsive to high dietary levels of folic acid (400 mcg./day), folic acid supplements in the range of 1-2 mg per day are usually effective in lowering elevated homocysteine concentrations.  It appears that certain people, due to their genetic endowment, require different amounts of dietary folic acid to properly metabolize homocysteine.

As fascinating as the evidence for homocysteine is, the exact mechanism(s) by which homocysteinemia does its job has been somewhat elusive.  One hypothesis has been that the damage comes from the toxic effect of homocysteine on endothelium by impairing the production of endothelium-derived relaxing factor.  Another line of thinking has suggested that homocysteine directly stimulates the proliferation of smooth-muscle cells in the endothelium.

Perhaps the most interesting theories of how homocysteinemia promotes problems comes from homocysteines relationship with copper and iron.  In the case of iron, it has been demonstrated that homocysteine induces iron-catalyzed lipid peroxidation.  Interestingly, vitamin E was very effective at slowing oxidation caused by homocysteine, providing further evidence for the protective effects of vitamin E.

Another documented result of elevated homocysteine concentrations is a detrimental effect on copper status, including decreased tissue levels of copper, decreased activities of copper-dependent antioxidant enzymes like ceruloplasmin and superoxide dismutase, decreased activity of glutathione, and a significant increase in lipid peroxidation in organ tissues.  Notably, some organs seem especially susceptible to lipid peroxidation resulting from homocysteinemia-induced copper deficiency, because other tissues such as the liver were not similarly affected.

As the data continues to accumulate, and homocysteinemia gains wider acceptance as a determinant of health risk, we can only hope that the population becomes as aware of its homocysteine concentration (both easily measured with a blood test); and most importantly, that vitamins B6, B12 and folic acid become routinely recommended by physicians as a safe and inexpensive measure to reduce this easily controlled risk-factor, namely homocysteinemia.

Folate and Chromosomes
The possible role of folic acid deficiency was first suggested by the evidence of chromosomal abnormalities present in folate-deficient people.  These chromosomal abnormalities were helped by folic acid supplementation.  Increased levels of chromosomal aberrations have been observed in lymphocytes from individuals with low serum levels of folic acid.

Unfortunately, as previously discussed, serum levels of folic acid may significantly underestimate the true incidence of subclinical folate deficiency.  The equivocal results found in some studies may result from this underestimation, as significant tissue deficiencies may exist in spite of normal serum folic acid levels.  In line with this reasoning, a study was conducted on the effect of smoking on folate levels in buccal mucosal cells.  The folate levels in these cells, taken from the mouth mucosa, were thought to more accurately reflect tissue folate status than serum levels of folic acid.  These researchers found that the correlation between plasma folate and oral mucosal folate was not of statistical significance, suggesting that plasma folate levels do not reflect the folate levels in oral mucosal cells.  In fact, smokers were twelve times more likely to have a buccal mucosal cell folate deficiency than were nonsmokers, despite the fact that their plasma folate levels were at the low end of the normal range and not considered deficient.  Although blood micronutrient levels are presumed to reflect tissue levels, data on tissue nutrient levels is limited.

Thus, the accumulating epidemiological evidence of folates role may seriously underestimate the role of folate, because almost all of these studies utilize the easily collected serum folate level.  It is likely that these studies may be showing us only the tip of the iceberg and that large studies utilizing tissue folate measurement would show a very strong association between localized tissue deficiencies of folate and the development of health problems.

Folate Supplementation
Because of all the evidence that most persons are consuming diets inadequate in folate content for optimum health, many people consume supplements containing folic acid.  Although estimates of the incidence of subclinical folate deficiency have varied, some research has suggested that it is widespread.  In one well-done study that examined metabolic evidence for folic acid deficiency (elevated homocysteine levels), in addition to the more commonly measured serum folic acid level, it was found that the incidence of metabolic evidence of folic acid deficiency is substantially higher than could be estimated from the serum concentration of folic acid.  While the incidence of low serum folic acid was found in only five percent of the subjects, metabolic evidence of folic acid deficiency was found in thirty percent.  It seems likely that subclinical deficiency is more common than thought, mainly because the commonly tested serum level of folic acid is not a good measure of true folate status.  This is especially relevant to persons with increased folic acid utilization and requirements such as smokers, drinkers, pregnant women, and the elderly.

The safety and toxicity of folic acid has been reviewed, and folic acid is generally regarded as non-toxic for normal humans.  There has been some concern expressed, however, that large amounts of folic acid (>1 mg./day) is not advised.  Although the above found little documented evidence of this actually occurring (one or two documented cases over a ten year period), persons taking folic acid supplements would be well advised to concurrently consume a vitamin B12 supplement.  Certainly the research supports the idea that folic acid supplementation of 200-1000 micrograms per day is safe for virtually all persons and that this level of supplementation can prevent or correct clinical and subclinical evidence of folate deficiency in the vast majority of persons.

Unfortunately, the optimal intake of folate is undetermined.  The supplemental form of folate, folic acid, is considered more bioavailable than many food folates.  Additionally, the necessary dietary intake to ensure both adequate serum and tissue folate levels in different groups of individuals (i.e. smokers) is unknown.  Based on the knowledge to date, 500 to 1000 micrograms per day of supplemental folic acid should be adequate and safe for most individuals.  Based on bioavailability studies, approximately twice this amount of food folates would be necessary.  Few of us do, however, consume this amount on a regular basis.  Given its safety and many potential benefits, it is hard to justify not supplementing with folic acid.  With all the potential benefits of folic acid, we can only hope for the day when it is required that foods be fortified with folic acid, perhaps along with vitamin B-12.  The benefits of this to the population at large, many of whom are consuming an inadequate amount of folate in their diet, could be enormous.

Warnings Information:

  • For dietary supplement use only,
  • Keep Folic Acid (folate) supplements out of reach of children,
  • Do not exceed recommended dosage,
  • If you have a bad reaction or side effects, discontinue use immediately,
  • When using Folic Acid (folate) supplements, please inform your physician,
  • If you are pregnant, lactating or have a medical condition, consult your health care professional before using this or any other nutritional supplement,
  • If negative side effects of allergic reaction occurs, discontinue immediately.

Folic Acid (folate) Supplements - Page 1 | Drinkers Cut canc Risk With Folate, Study Finds

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