Vitamin B6

Vitamin B₆ refers to a group of chemically very similar compounds which can be interconverted in biological systems. Vitamin B₆ is part of the vitamin B complex group, and its active form, Pyridoxal 5'-phosphate (PLP) serves as a cofactor in many enzyme reactions in amino acid, glucose, and lipid metabolism.

§Forms

Seven forms (vitamers) of vitamin B₆ are known:

• Pyridoxine (PN), the form 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 cannot be interconverted. Absorbed pyridoxamine is converted to PMP by pyridoxal kinase, which is further converted to PLP by pyridoxamine-phosphate transaminase or pyridoxine 5’-phosphate oxidase which also catalyzes the conversion of PNP to PLP. Pyridoxine 5’-phosphate oxidase is dependent on flavin mononucleotide (FMN) as a cofactor which is produced from riboflavin (vitamin B₂) i.e. in this biochemical pathway, dietary vitamin B₆ cannot be used without vitamin B₂.

§Functions

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

1. 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.
2. 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.
3. Serine racemase which synthesizes the neuromodulator serine is a PLP-dependent enzyme.
4. PLP is a coenzyme needed for the proper function of the enzymes cystathionine synthase and cystathionase. These enzymes work to transform methionine into cysteine.
5. 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.
6. PLP is required for the conversion of tryptophan to niacin, so low vitamin B₆ status impairs this conversion.

§Glucose metabolism

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.

§Lipid metabolism

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

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.

§Gene expression

PLP has been implicated in increasing or decreasing the expression of certain genes. Increased intracellular levels of the vitamin lead to a decrease in the transcription of glucocorticoids. Also, vitamin B₆ deficiency leads to the increased gene expression of albumin mRNA. Also, PLP influences expression of glycoprotein IIb by interacting with various transcription factors. The result is inhibition of platelet aggregation.

§Nutrition

§Food sources

Vitamin B₆ is widely distributed in foods in both its free and bound forms. Good sources include meats, whole-grain products (including cereals), 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.

The best natural sources include avocado, brewer's yeast, wheat bran, wheat germ, liver, kidney, heart, blackstrap molasses, milk, eggs, and beef.

§Dietary reference intakes

The Recommended Daily Allowance of the Institute of Medicine is 1,3 mg/d for a 19- to 50-year-old adult.

§Absorption and excretion

Vitamin B₆ is absorbed in the jejunum and ileum by 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 nonphosphorylated forms 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. An estimated 40â€"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 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.

§Deficiency

§Signs and symptoms

The classic clinical syndrome for vitamin B₆ deficiency is a seborrhoeic dermatitis-like eruption, atrophic glossitis with ulceration, angular cheilitis, conjunctivitis, intertrigo, and neurologic symptoms of somnolence, confusion, and neuropathy (due to impaired sphingosin synthesis) and sideroblastic anemia (due to impaired heme synthesis).

Less severe cases present with metabolic lesions associated with insufficient activities of the coenzyme PLP. The most prominent of the lesions is due to impaired tryptophan-niacin conversion. This can be detected based on urinary excretion of xanthurenic acid after an oral tryptophan load. Vitamin B₆ deficiency can also result in impaired transsulfuration of methionine to cysteine. The PLP-dependent transaminases and glycogen phosphorylase provide the vitamin with its role in gluconeogenesis, so deprivation of vitamin B₆ results in impaired glucose tolerance.

§Diagnosis

The assessment of vitamin B₆ status is essential, as the clinical signs and symptoms in less severe cases are not specific. The three biochemical tests most widely used are the activation coefficient for the erythrocyte enzyme aspartate aminotransferase, plasma PLP concentrations, and the urinary excretion of vitamin B₆ degradation products, specifically urinary PA. Of these, plasma PLP is probably the best single measure, because it reflects tissue stores. Plasma PLP less than 10nmol/l is indicative of vitamin B₆ deficiency. A PLP concentration greater than 20nmol/l has been chosen as a level of adequacy for establishing Estimated Average Requirements and Recommended Daily Allowances in the USA. Urinary PA is also an indicator of vitamin B₆ deficiency; levels of less than 3.0 mmol/day is suggestive of vitamin B₆ deficiency.

The classic syndrome for vitamin B₆ deficiency is rare, even in developing countries. A handful of cases were seen between 1952 and 1953, particularly in the United States, and occurred in a small percentage of infants who were fed a formula lacking in pyridoxine.

§Causes

A deficiency of vitamin B₆ alone is relatively uncommon and often occurs in association with other vitamins of the B complex. The elderly and alcoholics have an increased risk of vitamin B₆ deficiency, as well as other micronutrient deficiencies. Evidence exists for decreased levels of vitamin B₆ in women with type 1 diabetes and in patients with systemic inflammation, liver disease, rheumatoid arthritis, and those infected with HIV. Use of oral contraceptives and treatment with certain anticonvulsants, isoniazid, cycloserine, penicillamine, and hydrocortisone negatively impact vitamin B₆ status. Hemodialysis reduces vitamin B₆ plasma levels.

§Treatment

Treatment of vitamin B₆ deficiency lies with replacement, usually in the form of pyridoxine hydrochloride, orally, as a nasal spray, or for injection when in its solution form.

§Toxicity

Adverse effects have been documented from vitamin B₆ supplements, but never from food sources. Toxicologic animal studies identify specific destruction of the dorsal root ganglia which is documented in human cases of overdose 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, motor neuropathy may occur 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, so 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, little reason exists to exceed the RDI using supplements unless under medical supervision e.g. in treatment of primary hyperoxaluria.

§Medical 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.

The intake of vitamin B₆, from either diet or supplements, could cut the risk of Parkinson's disease in smokers by half, according to a prospective study from the Netherlands.

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.

Vitamin B₆ has been shown in at least two small-scale clinical studies to have a beneficial effect on the carpal tunnel syndrome, particularly in cases where no trauma or overuse etiology is known.

Pyridoxine may help balance hormonal changes in women and aid the immune system.

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.

Vitamin B₆ intake and PLP levels are inversely related to the risk of colon cancer. While the correlation with B₆ intake is 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 is an extremely rare genetic disorder characterized by intractable seizures in the prenatal and neonatal period that can be treated with pharmacological doses of vitamin B₆.

Pyridoxine is given to patients taking isoniazid (INH) to combat the toxic side effects of the drug.

In one form of homocystinuria, activity of the deficient enzyme can be enhanced by the administration of large doses of pyridoxine (100â€"1000 mg/day).

§History

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.

§References

§External links

• Facts about Vitamin B6 from Office of Dietary Supplements at National Institutes of Health
• The B6 database A database of B6-dependent enzymes at University of Parma
• COT statement on vitamin B6 (pyridoxine) toxicity (June 1997) (Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment (COT))
• Vitamin B6 at the US National Library of Medicine Medical Subject Headings (MeSH)