Vitamin B6 is a water-soluble vitamin and is part of the vitamin B complex group. Several forms of the vitamin are known, but pyridoxal phosphate (PLP) is the active form and acts as a cofactor in many enzyme reactions in amino acid, glucose and lipid metabolism.
- 1 History
- 2 Forms
- 3 Functions
- 4 Dietary reference intakes
- 5 Food sources
- 6 Absorption and excretion
- 7 Deficiency
- 8 Toxicity
- 9 Preventive roles and therapeutic uses
- 10 References
- 11 External links
In 1934, the Hungarian physician Paul Gyorgy discovered a substance that was able to cure a skin disease in rats (dermititis acrodynia). He named this substance vitamin B6. In 1938, Samuel Lepkovsky isolated vitamin B6 from rice bran. Harris and Folkers in 1939 determined the structure of pyridoxine, and, in 1945, Snell was able to show the two forms of vitamin B6, pyridoxal and pyridoxamine. Vitamin B6 was named pyridoxine to indicate its structural homology to pyridine.
Seven forms of this vitamin are known:
- Pyridoxine (PN), the form that is most commonly given as vitamin B6 supplement
- Pyridoxine 5'-phosphate (PNP)
- Pyridoxal (PL)
- Pyridoxal 5'-phosphate (PLP), the metabolically active form (sold as 'P-5-P' vitamin supplement)
- Pyridoxamine (PM)
- Pyridoxamine 5'-phosphate (PMP)
- 4-Pyridoxic acid (PA), the catabolite which is excreted in the urine
All forms except PA can be interconverted. 
Pyridoxal phosphate (PLP), the metabolically active form of vitamin B6, is involved in many aspects of macronutrient metabolism, neurotransmitter synthesis, histamine synthesis, hemoglobin synthesis and function and gene expression. PLP generally serves as a coenzyme (cofactor) for many reactions including decarboxylation, transamination, racemization, elimination, replacement and beta-group interconversion. The liver is the site for vitamin B6 metabolism.
Amino acid metabolism
- Pyridoxal phosphate (PLP) is a cofactor in the biosynthesis of five important neurotransmitters: serotonin, dopamine, epinephrine, norepinephrine and gamma-aminobutyric acid (GABA). PLP is also involved in the synthesis of histamine.
- Transaminases break down amino acids with PLP as a cofactor. The proper activity of these enzymes is crucial for the process of moving amine groups from one amino acid to another.
- Serine racemase which synthesizes the neuromodulator serine is a PLP-dependent enzyme.
- PLP is a coenzyme needed for the proper function of the enzymes cystathionine synthase and cystathionase. These enzymes work to transform methionine into cysteine.
- Selenomethionine is the primary dietary form of selenium. PLP is needed as a cofactor for the enzymes that allow selenium to be used from the dietary form. PLP also plays a cofactor role in releasing selenium from selenohomocysteine to produce hydrogen selenide, which can then be used to incorporate selenium into selenoproteins.
- PLP is required for the conversion of tryptophan to niacin, so low vitamin B6 status will impair this conversion.
Pyridoxal phosphate (PLP) is a required coenzyme of glycogen phosphorylase, the enzyme necessary for glycogenolysis to occur. PLP can catalyze transamination reactions that are essential for providing amino acids as a substrate for gluconeogenesis.
Pyridoxal phosphate (PLP) is an essential component of enzymes that facilitate the biosynthesis of sphingolipids. Particularly, the synthesis of ceramide requires PLP. In this reaction serine is decarboxylated and combined with palmitoyl-CoA to form sphinganine, which is combined with a fatty acyl-CoA to form dihydroceramide. Dihydroceramide is then further desaturated to form ceramide. In addition, the breakdown of sphingolipids is also dependent on vitamin B6 because S1P lyase, the enzyme responsible for breaking down sphingosine-1-phosphate, is also PLP-dependent.
Hemoglobin synthesis and function
Pyridoxal phosphate (PLP) aids in the synthesis of hemoglobin, by serving as a coenzyme for the enzyme ALA synthase. It also binds to two sites on hemoglobin to enhance the oxygen binding of hemoglobin.
Pyridoxal phosphate (PLP) has been implicated in increasing or decreasing the expression of certain genes. Increased intracellular levels of the vitamin will lead to a decrease in the transcription of glucocorticoids. Also, vitamin B6 deficiency will lead to the increased gene expression of albumin mRNA. Also, PLP will influence expression of glycoprotein IIb by interacting with various transcription factors. The result is inhibition of platelet aggregation.
Dietary reference intakes
Vitamin B6 is widely distributed in foods in both its free and bound forms. Good sources include meats, whole grain products, vegetables, nuts and bananas. Cooking, storage, and processing losses of vitamin B6 vary and in some foods may be more than 50%, depending on the form of vitamin present in the food. Plant foods lose the least during processing, as they contain mostly pyridoxine, which is far more stable than the pyridoxal or pyridoxamine found in animal foods. For example, milk can lose 30 to 70% of its vitamin B6 content when dried. Vitamin B6 is found in the germ and aleurone layer of grains, and milling results in the reduction of this vitamin in white flour. Freezing and canning are other food processing methods that result in the loss of vitamin B6 in foods.
Absorption and excretion
Vitamin B6 is absorbed in the jejunum and ileum via passive diffusion. With the capacity for absorption being so great, animals are able to absorb quantities much greater than necessary for physiological demands. The absorption of pyridoxal phosphate and pyridoxamine phosphate involves their dephosphorylation catalyzed by a membrane-bound alkaline phosphatase. Those products and non-phosphorylated vitamers in the digestive tract are absorbed by diffusion, which is driven by trapping of the vitamin as 5'-phosphates through the action of phosphorylation (by a pyridoxal kinase) in the jejunal mucosa. The trapped pyridoxine and pyridoxamine are oxidized to pyridoxal phosphate in the tissue.
The products of vitamin B6 metabolism are excreted in the urine, the major product of which is 4-pyridoxic acid. It has been estimated that 40–60% of ingested vitamin B6 is oxidized to 4-pyridoxic acid. Several studies have shown that 4-pyridoxic acid is undetectable in the urine of vitamin B6 deficient subjects, making it a useful clinical marker to assess the vitamin B6 status of an individual. Other products of vitamin B6 metabolism that are excreted in the urine when high doses of the vitamin have been given include pyridoxal, pyridoxamine, and pyridoxine and their phosphates. A small amount of vitamin B6 is also excreted in the feces.
Adverse effects have been documented from vitamin B6 supplements but never from food sources. This article discusses only the safety of the common supplemental form of vitamin B6, pyridoxine (for a full discussion please see pyridoxine). Toxicologic animal studies identify specific destruction of the dorsal root ganglia which is documented in human cases of overdosage of pyridoxine. Although it is a water-soluble vitamin and is excreted in the urine, doses of pyridoxine in excess of the RDI over long periods of time result in painful and ultimately irreversible neurological problems.
The primary symptoms are pain and numbness of the extremities. In severe cases, there may also be motor neuropathy with "slowing of motor conduction velocities, prolonged F wave latencies, and prolonged sensory latencies in both lower extremities" causing difficulty in walking. Sensory neuropathy typically develops at doses of pyridoxine in excess of 1,000 mg per day but adverse effects can occur with much less and, therefore, doses over 200 mg are not considered safe. Symptoms among women taking lower doses have been reported. Two reported cases of neuropathy with pyridoxine treatment of 24 and 40 mg/day may have been coincidental.
Existing authorisations and valuations vary considerably worldwide. In 1993, the European Community Scientific Committee on Food defined intakes of 50 mg of vitamin B6 per day as harmful and established a tolerable upper intake level of 25 mg/day for adults in 2000. The Expert Group on Vitamins and Minerals of the Food Standard Agency UK (UK EVM) derived a safe upper level (SUL) of 10 mg/day for a 60-kg adult in 2003. The tolerable upper limit has been set by the US FDA at 100 mg/day in 2000.
The nutrient reference values in Australia and New Zealand recommend an upper limit of 50 mg a day in adults. "The same figure was set for pregnancy and lactation as there is no evidence of teratogenicity at this level. The UL was set based on metabolic body size and growth considerations for all other ages and life stages except infancy. It was not possible to set a UL for infants, so intake is recommended in the form of food, milk or formula." "The ULs were set using results of studies involving long-term oral administration of pyridoxine at doses of less than 1g/day (Berger & Schaumburg 1984, Bernstein & Lobitz 1988, Dalton 1985, Dalton & Dalton 1987, Del Tredici et al 1985, FNB:IOM 1998, Parry & Bredesen 1985). A NOAEL (No-observed-adverse-effect level) of 200 mg/day was identified from the studies of Bernstein & Lobitz (1988) and Del Tredici et al (1985). These studies involved subjects who had generally been on the supplements for five to six months or less. The study of Dalton and Dalton (1987), however, suggested the symptoms might take substantially longer than this to appear. In this latter retrospective survey, subjects who reported symptoms had been on supplements for 2.9 years, on average. Those reporting no symptoms had taken supplements for 1.9 years."
Because no placebo-controlled studies show therapeutic benefits of high doses of pyridoxine, and the well-documented occurrence of significant toxic effects, there is little reason to exceed the RDI using supplements unless under medical supervision e.g. in treatment of primary hyperoxaluria.
Recently there is a growing number of consumer reports indicating that B6 can cause severe toxicity and permanent disability, even at RDI levels. 
Preventive roles and therapeutic uses
Vitamin B6 has been used to treat nausea and vomiting in early pregnancy for decades, commonly in conjunction with other medications such as metoclopramide or doxylamine. Alone, it has been found safe and effective, though any woman's prenatal caregiver must help guide treatment for these symptoms.
At least one preliminary study has found this vitamin may increase dream vividness or the ability to recall dreams. This effect is possibly due to the role this vitamin plays in the conversion of tryptophan to serotonin. Anecdotal evidence suggests supplemental vitamin B6 may be associated with lucid dreaming.
Pyridoxine has a role in preventing heart disease. Without enough pyridoxine, the compound homocysteine builds up in the body. Homocysteine damages blood vessel linings, setting the stage for plaque buildup when the body tries to heal the damage. Vitamin B6 prevents this buildup, thereby reducing the risk of heart attack. Pyridoxine lowers blood pressure and blood cholesterol levels and keeps blood platelets from sticking together. All of these properties work to keep heart disease at bay.[unreliable source?]
Nutritional supplementation with high dose vitamin B6 and magnesium is one of the most popular alternative medicine choices for autism, but randomised control trials have had mixed results and small sample sizes mean no conclusions can be drawn as to the efficacy of this treatment.
Some studies suggest the vitamin B6-magnesium combination can also help attention deficit disorder, citing improvements in hyperactivity, hyperemotivity/aggressiveness and improved school attention.
If people are marginally deficient in vitamin B6, they may be more susceptible to carpal tunnel syndrome (CTS). CTS is characterized by pain and tingling in the wrists after performing repetitive movements or otherwise straining the wrist regularly. Vitamin B6 has been shown in at least two small-scale clinical studies to have a beneficial effect on the syndrome, particularly in cases where no trauma or overuse etiology is known.
Vitamin B6 has long been publicized as a cure for premenstrual syndrome (PMS). Study results conflict as to which symptoms are eased, but most confirm women who take B6 supplements have reductions in bloating, breast pain, and premenstrual acne flare, a condition in which pimples break out about a week before a woman's period begins. Strong evidence suggests pyridoxine supplementation, starting 10 days before the menstrual period, prevents most pimples from forming. This effect is caused by the vitamin's role in hormone and prostaglandin regulation. Skin blemishes are typically caused by a hormone imbalance, which vitamin B6 helps to regulate.[unreliable source?]
Mental depression is another condition which may result from low vitamin B6 intake. Because of pyridoxine's role in serotonin and other neurotransmitter production, supplementation often helps depressed people feel better, and their moods improve significantly. It may also help improve memory in older adults.[unreliable source?] However, the effectiveness as treatment for PMS, PMDD, and clinical depression is debatable.
Ingestion of vitamin B6 possibly can alleviate some of the many symptoms of an alcoholic hangover and morning sickness from pregnancy. This might result from its mild diuretic effect. Though the mechanism is not known, results show pyridoxamine has therapeutic effects in clinical trials for diabetic nephropathy.
Larsson et al. have shown vitamin B6 intake and pyridoxal phosphate (PLP) levels are inversely related to the risk of colon cancer. While in their study the correlation with B6 intake was moderate, it was quite dramatic with PLP levels, where the risk of colon cancer was decreased by nearly half.
Vitamin B6 is also known to increase the metabolism of Parkinson's medications, such as levodopa, and should be used cautiously.
Pyridoxine-dependent epilepsy (PDE) epilepsy is an extremely rare genetic disorder characterized by intractable seizures in the prenatal and neonatal period that can be treated with pharmacological doses Vitamin B6.
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