Fundamentals of Human Nutrition/Vitamin B6
8.6 Vitamin B6
Vitamin B6 is a water-soluble vitamin that was first isolated in the 1930s. There are three traditionally considered forms of vitamin B6: pyridoxal (PL), pyridoxine (PN), pyridoxamine (PM). The phosphate ester derivative pyridoxal 5'-phosphate (PLP) is the principal coenzyme form and has the most importance in human metabolism (1-3).
Vitamin B6 must be obtained from the diet because humans cannot synthesize it. PLP plays a vital role in the function of approximately 100 enzymes that catalyze essential chemical reactions in the human body (1-5). For example, PLP functions as a coenzyme for glycogen phosphorylase, an enzyme that catalyzes the release of glucose from stored glycogen. Much of the PLP in the human body is found in muscle bound to glycogen phosphorylase. PLP is also a coenzyme for reactions used to generate glucose from amino acids, a process known as gluconeogenesis (4, 5).
Nervous system function
In the brain, the synthesis of the neurotransmitter, serotonin, from the amino acid, tryptophan, is catalyzed by a PLP-dependent enzyme. Other neurotransmitters, such as dopamine, norepinephrine and gamma-aminobutyric acid (GABA), are also synthesized using PLP-dependent enzymes (4).
Red blood cell formation and function
PLP functions as a coenzyme in the synthesis of heme, an iron-containing component of hemoglobin. Hemoglobin is found in red blood cells and is critical to their ability to transport oxygen throughout the body. Both PL and PLP are able to bind to the hemoglobin molecule and affect its ability to pick up and release oxygen. However, the impact of this on normal oxygen delivery to tissues is not known (4).
The human requirement for another B vitamin, niacin, can be met in part by the conversion of the essential amino acid, tryptophan, to niacin, as well as through dietary intake. PLP is a coenzyme for a critical reaction in the synthesis of niacin from tryptophan; thus, adequate vitamin B6 decreases the requirement for dietary niacin (4).
Steroid hormones, such as estrogen and testosterone, exert their effects in the body by binding to steroid hormone receptors in the nucleus of the cell and altering gene transcription. PLP binds to steroid receptors in a manner that inhibits the binding of steroid hormones, thus decreasing their effects. The binding of PLP to steroid receptors for estrogen, progesterone, testosterone, and other steroid hormones suggests that the vitamin B6 status of an individual may have implications for diseases affected by steroid hormones, including breast cancer and prostate cancers (4).
Nucleic acid synthesis
PLP serves as a coenzyme for a key enzyme involved in the mobilization of single-carbon functional groups (one-carbon metabolism). Such reactions are involved in the synthesis of nucleic acids. The effect of vitamin B6 deficiency on the function of the immune system may be partly related to the role of PLP in one-carbon metabolism (see Disease Prevention).
Homocysteine and cardiovascular disease
Even moderately elevated levels of homocysteine in the blood have been associated with increased risk for cardiovascular disease, including heart disease and stroke (8). During protein digestion, amino acids, including methionine, are released. Homocysteine is an intermediate in the metabolism of methionine. Healthy individuals utilize two different pathways to metabolize homocysteine. One pathway converts homocysteine back to methionine and is dependent on folic acid and vitamin B12. The other pathway converts homocysteine to the amino acid cysteine and requires two vitamin B6(PLP)-dependent enzymes. Thus, the amount of homocysteine in the blood is regulated by at least three vitamins: folic acid, vitamin B12, and vitamin B6 (diagram). Several large observational studies have demonstrated an association between low vitamin B6 intake or status with increased blood homocysteine levels and increased risk of cardiovascular diseases. A large prospective study found the risk of heart disease in women who consumed, on average, 4.6 mg of vitamin B6 daily was only 67% of the risk in women who consumed an average of 1.1 mg daily (9). Another large prospective study found higher plasma levels of PLP were associated with a decreased risk of cardiovascular disease independent of homocysteine levels (10). Further, several studies have reported that low plasma PLP status is a risk factor for coronary artery disease (11-13). In contrast to folic acid supplementation, studies supplementing individuals with only vitamin B6 have not resulted in significant decreases in basal (fasting) levels of homocysteine. However, one study found that vitamin B6 supplementation was effective in lowering blood homocysteine levels after an oral dose of methionine (methionine load test) was given (14), suggesting vitamin B6 may play a role in the metabolism of homocysteine after meals.
Low vitamin B6 intake and nutritional status have been associated with impaired immune function, especially in the elderly. Decreased production of immune system cells known as lymphocytes, as well as decreased production of an important immune system protein called interleukin-2, have been reported in vitamin B6 deficient individuals (15). Restoration of vitamin B6 status has resulted in normalization of lymphocyte proliferation and interleukin-2 production, suggesting that adequate vitamin B6 intake is important for optimal immune system function in older individuals (15, 16). However, one study found that the amount of vitamin B6 required to reverse these immune system impairments in the elderly was 2.9 mg/day for men and 1.9 mg/day for women; these vitamin B6 requirements are higher than the current RDA (15).
A few studies have associated cognitive decline in the elderly or Alzheimer's disease with inadequate nutritional status of folic acid, vitamin B12, and vitamin B6 and thus, elevated levels of homocysteine (17). One observational study found that higher plasma vitamin B6 levels were associated with better performance on two measures of memory, but plasma vitamin B6 levels were unrelated to performance on 18 other cognitive tests (18). Similarly, a double-blind, placebo-controlled study in 38 healthy elderly men found that vitamin B6 supplementation improved memory but had no effect on mood or mental performance (19). Further, a placebo-controlled trial in 211 healthy younger, middle-aged, and older women found that vitamin B6 supplementation (75 mg/day) for five weeks improved memory performance in some age groups but had no effect on mood (20). Recently, a systematic review of randomized trials concluded that there is inadequate evidence that supplementation with vitamin B6, vitamin B12, or folic acid improves cognition in those with normal or impaired cognitive function (21). Because of mixed findings, it is presently unclear whether supplementation with B vitamins might blunt cognitive decline in the elderly. Further, it is not known if marginal B vitamin deficiencies, which are relatively common in the elderly, even contribute to age-associated declines in cognitive function, or whether both result from processes associated with aging and/or disease.
A large prospective study examined the relationship between vitamin B6 intake and the occurrence of symptomatic kidney stones in women. A group of more than 85,000 women without a prior history of kidney stones were followed over 14 years and those who consumed 40 mg or more of vitamin B6 daily had only two thirds the risk of developing kidney stones compared with those who consumed 3 mg or less (22). However, in a group of more than 45,000 men followed over six years, no association was found between vitamin B6 intake and the occurrence of kidney stones (23). Limited data have shown that supplementation of vitamin B6 at levels higher than the tolerable upper intake level (100 mg/day) decreases elevated urinary oxalate levels, an important determinant of calcium oxalate kidney stone formation in some individuals. However, it is less clear that supplementation actually resulted in decreased formation of calcium oxalate kidney stones. Presently, the relationship between vitamin B6 intake and the risk of developing kidney stones requires further study before any recommendations can be made.
Vitamin B6 supplements at pharmacologic doses (i.e., doses much larger than those needed to prevent deficiency) have been used in an attempt to treat a wide variety of conditions, some of which are discussed below. In general, well designed, placebo-controlled studies have shown little evidence that large supplemental doses of vitamin B6 are beneficial (24). Side effects of oral contraceptives Because vitamin B6 is required for the metabolism of the amino acid tryptophan, the tryptophan load test (an assay of tryptophan metabolites after an oral dose of tryptophan) was used as a functional assessment of vitamin B6 status. Abnormal tryptophan load tests in women taking high-dose oral contraceptives in the 1960s and 1970s suggested that these women were vitamin B6 deficient. Abnormal results in the tryptophan load test led a number of clinicians to prescribe high doses (100-150 mg/day) of vitamin B6 to women in order to relieve depression and other side effects sometimes experienced with oral contraceptives. However, most other indices of vitamin B6 status were normal in women on high-dose oral contraceptives, and it is unlikely that the abnormality in tryptophan metabolism was due to vitamin B6 deficiency (24). A more recent placebo-controlled study in women on the lower dose oral contraceptives, which are commonly prescribed today, found that doses up to 150 mg/day of vitamin B6 (pyridoxine) had no benefit in preventing side effects, such as nausea, vomiting, dizziness, depression, and irritability (25).
Premenstrual syndrome (PMS)
The use of vitamin B6 to relieve the side effects of high-dose oral contraceptives led to the use of vitamin B6 in the treatment of premenstrual syndrome (PMS). PMS refers to a cluster of symptoms, including but not limited to fatigue, irritability, moodiness/depression, fluid retention, and breast tenderness, that begin sometime after ovulation (mid-cycle) and subside with the onset of menstruation (the monthly period). A review of 12 placebo-controlled double-blind trials on vitamin B6 use for PMS treatment concluded that evidence for a beneficial effect was weak (26). A more recent review of 25 studies suggested that supplemental vitamin B6, up to 100 mg/day, may be of value to treat PMS; however, only limited conclusions could be drawn because most of the studies were of poor quality (27).
Because a key enzyme in the synthesis of the neurotransmitters serotonin and norepinephrine is PLP-dependent, it has been suggested that vitamin B6 deficiency may lead to depression. However, clinical trials have not provided convincing evidence that vitamin B6 supplementation is an effective treatment for depression (24, 28), though vitamin B6 may have therapeutic efficacy in premenopausal women (28). Morning sickness (nausea and vomiting in pregnancy) Vitamin B6 has been used since the 1940s to treat nausea during pregnancy. Vitamin B6 was included in the medication Bendectin, which was prescribed for the treatment of morning sickness and later withdrawn from the market due to unproven concerns that it increased the risk of birth defects. Vitamin B6 itself is considered safe during pregnancy and has been used in pregnant women without any evidence of fetal harm (29). The results of two double-blind, placebo-controlled trials that used 25 mg of pyridoxine every eight hours for three days (30) or 10 mg of pyridoxine every eight hours for five days (29) suggest that vitamin B6 may be beneficial in alleviating morning sickness. Each study found a slight but significant reduction in nausea or vomiting in pregnant women. A recent systematic review of placebo-controlled trials on nausea during early pregnancy found vitamin B6 to be somewhat effective (31). However, it should be noted that morning sickness also resolves without any treatment, making it difficult to perform well-controlled trials.
Carpal tunnel syndrome
Carpal tunnel syndrome causes numbness, pain, and weakness of the hand and fingers due to compression of the median nerve at the wrist. It may result from repetitive stress injury of the wrist or from soft tissue swelling, which sometimes occurs with pregnancy or hypothyroidism. Several early studies by the same investigator suggested that vitamin B6 status was low in individuals with carpal tunnel syndrome and that supplementation with 100-200 mg/day over several months was beneficial (32, 33). A recent study in men not taking vitamin supplements found that decreased blood levels of PLP were associated with increased pain, tingling, and nocturnal wakening, all symptoms of carpal tunnel syndrome (34). Studies using electrophysiological measurements of median nerve conduction have largely failed to find an association between vitamin B6 deficiency and carpal tunnel syndrome. While a few trials have noted some symptomatic relief with vitamin B6 supplementation, double-blind, placebo-controlled trials have not generally found vitamin B6 to be effective in treating carpal tunnel syndrome (24, 35).
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