Vitamin B6
Vitamin B6 is one of the B vitamins, and thus an essential nutrient.[1][2][3][4] The term refers to a group of six chemically similar compounds, i.e., "vitamers", which can be interconverted in biological systems. Its active form, pyridoxal 5′-phosphate, serves as a coenzyme in more than 140 enzyme reactions in amino acid, glucose, and lipid metabolism.[1][2][3]
This article is about the group of vitamers. For the dietary supplement, see Pyridoxine.Vitamin B6
Plants synthesize pyridoxine as a means of protection from the UV-B radiation found in sunlight[5] and for the role it plays in the synthesis of chlorophyll.[6] Animals cannot synthesize any of the various forms of the vitamin, and hence must obtain it via diet, either of plants, or of other animals. There is some absorption of the vitamin produced by intestinal bacteria, but this is not sufficient to meet dietary needs. For adult humans, recommendations from various countries' food regulatory agencies are in the range of 1.0 to 2.0 milligrams (mg) per day. These same agencies also recognize ill effects from intakes that are too high, and so set safe upper limits, ranging from as low as 25 mg/day to as high as 100 mg/day depending on the country. Beef, pork, fowl and fish are generally good sources; dairy, eggs, mollusks and crustaceans also contain vitamin B6, but at lower levels. There is enough in a wide variety of plant foods so that a vegetarian or vegan diet does not put consumers at risk for deficiency.[7]
Dietary deficiency is rare. Classic clinical symptoms include rash and inflammation around the mouth and eyes, plus neurological effects that include drowsiness and peripheral neuropathy affecting sensory and motor nerves in the hands and feet. In addition to dietary shortfall, deficiency can be the result of anti-vitamin drugs. There are also rare genetic defects that can trigger vitamin B6 deficiency-dependent epileptic seizures in infants. These are responsive to pyridoxal 5'-phosphate therapy.[8]
Absorption, metabolism and excretion[edit]
Vitamin B6 is absorbed in the jejunum of the small intestine by passive diffusion.[1][4] Even extremely large amounts are well absorbed. Absorption of the phosphate forms involves their dephosphorylation catalyzed by the enzyme alkaline phosphatase.[15] Most of the vitamin is taken up by the liver. There, the dephosphorylated vitamins are converted to the phosphorylated PLP, PNP and PMP, with the two latter converted to PLP. In the liver, PLP is bound to proteins, primarily albumin. The PLP-albumin complex is what is released by the liver to circulate in plasma.[4] Protein-binding capacity is the limiting factor for vitamin storage. Total body stores, the majority in muscle, with a lesser amount in liver, have been estimated to be in the range of 61 to 167 mg.[4]
Enzymatic processes utilize PLP as a phosphate-donating cofactor. PLP is restored via a salvage pathway that requires three key enzymes, pyridoxal kinase, pyridoxine 5'-phosphate oxidase, and phosphatases.[6][8] Inborn errors in the salvage enzymes are known to cause inadequate levels of PLP in the cell, particularly in neuronal cells. The resulting PLP deficiency is known to cause or implicated in several pathologies, most notably infant epileptic seizures.[8]
The half-life of vitamin B6 varies according to different sources: one source suggests that the half-life of pyridoxine is up to 20 days,[38] while another source indicates half-life of vitamin B6 is in range of 25 to 33 days.[39] After considering the different sources, it can be concluded that the half-life of vitamin B6 is typically measured in several weeks.[38][39]
The end-product of vitamin B6 catabolism is 4-pyridoxic acid, which makes up about half of the B6 compounds in urine. 4-Pyridoxic acid is formed by the action of aldehyde oxidase in the liver. Amounts excreted increase within 1–2 weeks with vitamin supplementation and decrease as rapidly after supplementation ceases.[4][40] Other vitamin forms excreted in the urine include pyridoxal, pyridoxamine and pyridoxine, and their phosphates. When large doses of pyridoxine are given orally, the proportion of these other forms increases. A small amount of vitamin B6 is also excreted in the feces. This may be a combination of unabsorbed vitamin and what was synthesized by large intestine microbiota.[4]
Deficiency[edit]
Signs and symptoms[edit]
The classic clinical syndrome for vitamin B6 deficiency is a seborrheic dermatitis-like eruption, atrophic glossitis with ulceration, angular cheilitis, conjunctivitis, intertrigo, abnormal electroencephalograms, microcytic anemia (due to impaired heme synthesis), and neurological symptoms of somnolence, confusion, depression, and neuropathy (due to impaired sphingosine synthesis).[1]
In infants, a deficiency in vitamin B6 can lead to irritability, abnormally acute hearing, and convulsive seizures.[1]
Less severe cases present with metabolic disease associated with insufficient activity of the coenzyme pyridoxal 5' phosphate (PLP).[1] 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.[1][15]
Diagnosis[edit]
The assessment of vitamin B6 status is essential, as the clinical signs and symptoms in less severe cases are not specific.[41] The three biochemical tests most widely used are plasma PLP concentrations, the activation coefficient for the erythrocyte enzyme aspartate aminotransferase, 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 of less than 10 nmol/L is indicative of vitamin B6 deficiency.[40] A PLP concentration greater than 20 nmol/L has been chosen as a level of adequacy for establishing Estimated Average Requirements and Recommended Daily Allowances in the USA.[4] Urinary PA is also an indicator of vitamin B6 deficiency; levels of less than 3.0 mmol/day is suggestive of vitamin B6 deficiency.[40] Other methods of measurement, including UV spectrometric, spectrofluorimetric, mass spectrometric, thin-layer and high-performance liquid chromatographic, electrophoretic, electrochemical, and enzymatic, have been developed.[40][42]
The classic clinical symptoms for vitamin B6 deficiency are rare, even in developing countries. A handful of cases were seen between 1952 and 1953, particularly in the United States, having occurred in a small percentage of infants who were fed a formula lacking in pyridoxine.[43]
Causes[edit]
A deficiency of vitamin B6 alone is relatively uncommon and often occurs in association with other vitamins of the B complex. 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.[44][45] Use of oral contraceptives and treatment with certain anticonvulsants, isoniazid, cycloserine, penicillamine, and hydrocortisone negatively impact vitamin B6 status.[1][46][47] Hemodialysis reduces vitamin B6 plasma levels.[48]
Research[edit]
Observational studies suggested an inverse correlation between a higher intake of vitamin B6 and all cancers, with the strongest evidence for gastrointestinal cancers. However, evidence from a review of randomized clinical trials did not support a protective effect. The authors noted that high B6 intake may be an indicator of higher consumption of other dietary protective micronutrients.[57] A review and two observational trials reporting lung cancer risk reported that serum vitamin B6 was lower in people with lung cancer compared to people without lung cancer, but did not incorporate any intervention or prevention trials.[58][59][60]
According to a prospective cohort study the long-term use of vitamin B6 from individual supplement sources at greater than 20 mg per day, which is more than ten times the adult male RDA of 1.7 mg/day, was associated with an increased risk for lung cancer among men. Smoking further elevated this risk.[61] However, a more recent review of this study suggested that a causal relationship between supplemental vitamin B6 and an increased lung cancer risk cannot be confirmed yet.[62]
For coronary heart disease, a meta-analysis reported lower relative risk for a 0.5 mg/day increment in dietary vitamin B6 intake.[63] As of 2021, there were no published reviews of randomized clinical trials for coronary heart disease or cardiovascular disease. In reviews of observational and intervention trials, neither higher vitamin B6 concentrations[64] nor treatment[65] showed any significant benefit on cognition and dementia risk. Low dietary vitamin B6 correlated with a higher risk of depression in women but not in men.[66] When treatment trials were reviewed, no meaningful treatment effect for depression was reported, but a subset of trials in pre-menopausal women suggested a benefit, with a recommendation that more research was needed.[67] The results of several trials with children diagnosed as having autism spectrum disorder (ASD) treated with high dose vitamin B6 and magnesium did not result in treatment effect on the severity of symptoms of ASD.[68]