Plants synthesize pyridoxine as a means of protection from theUV-B radiation found in sunlight[5] and for the role it plays in the synthesis ofchlorophyll.[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 byintestinal 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 2.0milligrams (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 12 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 avegetarian orvegan diet does not put consumers at risk fordeficiency.[7]
Dietary deficiency is rare. Classic clinical symptoms includerash andinflammation around the mouth and eyes, plus neurological effects that include drowsiness andperipheral neuropathy affectingsensory andmotor nerves in the hands and feet. In addition to dietary shortfall, deficiency can be the result ofanti-vitamin drugs. There are also rare genetic defects that can trigger vitamin B6 deficiency-dependentepileptic seizures in infants. These are responsive to pyridoxal 5'-phosphate therapy.[8]
Because of its chemical stability, pyridoxine hydrochloride is the form most commonly given as vitamin B6 dietary supplement. Absorbed pyridoxine (PN) is converted to pyridoxamine 5'-phosphate (PMP) by the enzymepyridoxal kinase, with PMP further converted to pyridoxal 5'-phosphate (PLP), the metabolically active form, by the enzymespyridoxamine-phosphate transaminase orpyridoxine 5'-phosphate oxidase, the latter of which also catalyzes the conversion of pyridoxine 5′-phosphate (PNP) to PLP.[3][9] Pyridoxine 5'-phosphate oxidase is dependent onflavin mononucleotide (FMN) as a cofactor produced fromriboflavin (vitamin B2). For degradation, in a non-reversible reaction, PLP iscatabolized to 4-pyridoxic acid, which is excreted in urine.[3]
Two pathways for PLP are currently known: one requires deoxyxylulose 5-phosphate (DXP), while the other does not, hence they are known as DXP-dependent and DXP-independent. These pathways have been studied extensively inEscherichia coli[10] andBacillus subtilis, respectively. Despite the disparity in the starting compounds and the different number of steps required, the two pathways possess many commonalities.[11] The DXP-dependent pathway:
The starting material is either the amino acidalanine, orpropionic acid converted into alanine viahalogenation andamination. Then, the procedure accomplishes the conversion of the amino acid into pyridoxine through the formation of anoxazole intermediate followed by aDiels–Alder reaction, with the entire process referred to as the "oxazole method".[9][12] The product used in dietary supplements andfood fortification ispyridoxine hydrochloride, the chemically stablehydrochloride salt of pyridoxine.[13] Pyridoxine is converted in the liver into the metabolically active coenzyme form pyridoxal 5'-phosphate. At present, while the industry mainly utilizes the oxazole method, there is research exploring means of using less toxic and dangerous reagents in the process.[14] Fermentative bacterial biosynthesis methods are also being explored, but are not yet scaled up for commercial production.[13]
Transaminases break down amino acids with PLP as a cofactor. The proper activity of these enzymes is crucial for the process of movingamine groups from one amino acid to another. To function as a transaminase coenzyme, PLP bound to alysine of the enzyme then binds to a free amino acid via formation of aSchiff's base. The process then dissociates the amine group from the amino acid, releasing aketo acid, then transfers the amine group to a different keto acid to create a new amino acid.[3]
Selenomethionine is the primary dietary form ofselenium. 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 producehydrogen selenide, which can then be used to incorporate selenium intoselenoproteins.
PLP is required for the conversion oftryptophan toniacin, so low vitamin B6 status impairs this conversion.[15]
PLP is a required coenzyme ofglycogen phosphorylase, the enzyme necessary forglycogenolysis.Glycogen serves as a carbohydrate storage molecule, primarily found in muscle, liver and brain. Its breakdown frees up glucose for energy.[6] PLP also catalyzes transamination reactions that are essential for providing amino acids as a substrate forgluconeogenesis, the biosynthesis of glucose.[15]
PLP is an essential component of enzymes that facilitate the biosynthesis ofsphingolipids.[15] Particularly, the synthesis ofceramide requires PLP. In this reaction, serine is decarboxylated and combined withpalmitoyl-CoA to formsphinganine, which is combined with a fattyacyl-CoA to form dihydroceramide. This compound is thenfurther desaturated to form ceramide. In addition, the breakdown of sphingolipids is also dependent on vitamin B6 becausesphingosine-1-phosphate lyase, the enzyme responsible for breaking downsphingosine-1-phosphate, is also PLP-dependent.
PLP aids in the synthesis ofhemoglobin, by serving as a coenzyme for the enzymeaminolevulinic acid synthase.[6] It also binds to two sites on hemoglobin to enhance the oxygen binding of hemoglobin.[15]
PLP has been implicated in increasing or decreasing the expression of certaingenes. Increased intracellular levels of the vitamin lead to a decrease in thetranscription ofglucocorticoids. Vitamin B6 deficiency leads to the increasedgene expression ofalbuminmRNA. Also, PLP influences expression ofglycoprotein IIb by interacting with varioustranscription factors; the result is inhibition ofplatelet aggregation.[15]
Plant synthesis of vitamin B6 contributes to protection from sunlight.Ultraviolet-B radiation (UV-B) from sunlight stimulates plant growth, but in high amounts can increase production of tissue-damagingreactive oxygen species (ROS), i.e.,oxidants. UsingArabidopsis thaliana (common name: thale cress), researchers demonstrated that UV-B exposure increased pyridoxine biosynthesis, but in a mutant variety, pyridoxine biosynthesis capacity was notinducible, and as a consequence, ROS levels,lipid peroxidation, and cell proteins associated with tissue damage were all elevated.[5][16][17] Biosynthesis ofchlorophyll depends on aminolevulinic acid synthase, a PLP-dependent enzyme that usessuccinyl-CoA andglycine to generateaminolevulinic acid, a chlorophyll precursor.[6] In addition, plant mutants with severely limited capacity to synthesize vitamin B6 have stunted root growth, because synthesis ofplant hormones such asauxin require the vitamin as an enzyme cofactor.[6]
Overconsumption of seeds fromGinkgo biloba can deplete vitamin B6, because theginkgotoxin is an anti-vitamin (vitamin antagonist). Symptoms include vomiting and generalized convulsions. Ginkgo seed poisoning can be treated with vitamin B6.[20][21]
The USNational Academy of Medicine updatedDietary Reference Intakes for many vitamins in 1998. Recommended Dietary Allowances (RDAs), expressed as milligrams per day, increase with age from 1.2 to 1.5 mg/day for women and from 1.3 to 1.7 mg/day for men. The RDA for pregnancy is 1.9 mg/day, forlactation, 2.0 mg/day. For children ages 1–13 years the RDA increases with age from 0.5 to 1.0 mg/day. As for safety, ULs for vitamins and minerals are identified when evidence is sufficient. In the case of vitamin B6 the US-established adult UL was set at 100 mg/day.[4]
The EFSA refers to the collective set of information as Dietary Reference Values, with Population Reference Intake (PRI) instead of RDA. For women and men ages 15 and older the PRI is set at 1.6 and 1.7 mg/day, respectively; for pregnancy 1.8 mg/day, for lactation 1.7 mg/day. For children ages 1–14 years the PRIs increase with age from 0.6 to 1.4 mg/day.[23] The EFSA also reviewed the safety question and in 2023 set an upper limit for vitamin B6 of 12 mg/day for adults, with lower amounts ranging from 2.2 to 10.7 mg/day for infants and children, depending on age.[22] This replaced the adult UL set in 2008 at 25 mg/day.[24]
The JapaneseMinistry of Health, Labour and Welfare updated its vitamin and mineral recommendations in 2015. The adult RDAs are at 1.2 mg/day for women 1.4 mg/day for men. The RDA for pregnancy is 1.4 mg/day, for lactation is 1.5 mg/day. For children ages 1–17 years the RDA increases with age from 0.5 to 1.5 mg/day. The adult UL was set at 40–45 mg/day for women and 50–60 mg/day for men, with the lower values in those ranges for adults over 70 years of age.[25]
Adverse effects have been documented from vitamin B6 dietary supplements, but never from food sources. Even though it is a water-soluble vitamin and is excreted in the urine, doses of pyridoxine in excess of the dietary upper limit (UL) over long periods cause painful and ultimately irreversible neurological problems.[4] The primary symptoms are pain and numbness of the extremities. In severe cases, motor neuropathy may occur with "slowing of motor conduction velocities, prolongedF wave latencies, and prolonged sensory latencies in both lower extremities", causing difficulty in walking. Sensoryneuropathy typically develops at doses of pyridoxine in excess of 1,000 mg per day.[4] As noted above, in 2023 the European Food Safety Commission set an adult UL at 12 mg/day.[22] While Australia has set an upper limit of 50 mg/day, theTherapeutic Goods Administration requires a label warning about peripheral neuropathy if the daily dose is predicted to exceed 10 mg/day.[26][27]
For US food and dietary supplement labeling purposes the amount in a serving is expressed as a percent of Daily Value. For vitamin B6 labeling purposes 100% of the Daily Value was 2.0 mg, but as of May 27, 2016, it was revised to 1.7 mg to bring it into agreement with the adult RDA.[28][29] A table of the old and new adult daily values is provided atReference Daily Intake.
Bacteria residing in thelarge intestine are known to synthesize B-vitamins, including B6, but the amounts are not sufficient to meet host requirements, in part because the vitamins are competitively taken up by non-synthesizing bacteria.[30]
Vitamin B6 is found in a wide variety of foods. In general, meat, fish and fowl are good sources, but dairy foods and eggs are not (table).[31][32] Crustaceans and mollusks contain about 0.1 mg/100 grams. Fruit (apples, oranges, pears) contain less than 0.1 mg/100g.[32]
Bioavailability from a mixed diet (containing animal- and plant-sourced foods) is estimated at being 75% – higher for PLP from meat, fish and fowl, lower from plants, as those are mostly in the form of pyridoxineglucoside, which has approximately half the bioavailability of animal-sourced B6 because removal of the glucoside by intestinal cells is not 100% efficient.[4] Given lower amounts and lower bioavailability of the vitamin from plants there was a concern that a vegetarian or vegan diet could cause a vitamin deficiency state. However, the results from a population-based survey conducted in the U.S. demonstrated that despite a lower vitamin intake, serum PLP was not significantly different between meat-eaters and vegetarians, suggesting that a vegetarian diet does not pose a risk for vitamin B6 deficiency.[7]
Cooking, storage, and processing losses vary, and in some foods may be more than 50% depending on the form of vitamin present in the food.[3] Plant foods lose less during processing, as they contain pyridoxine, which is more stable than the pyridoxal or pyridoxamine forms found in animal-sourced foods. For example, milk can lose 30–70% of its vitamin B6 content whendried.[15] The vitamin is found in thegerm andaleurone layer of grains, so there is more in grains from which these layers have not been removed, for example more inwhole wheat bread than inwhite wheat bread, and more inbrown rice than inwhite rice.[32]
Most values shown in the table are rounded to nearest tenth of a milligram:
As of 2024, eighteen countries require food fortification of wheat flour,maize flour or rice with vitamin B6 as pyridoxine hydrochloride. Most of these are in southeast Africa or Central America. The amounts stipulated range from 3.0 to 6.5 mg/kg. An additional six countries, including India, have a voluntary fortification program. India stipulates 2.0 mg/kg.[33]
In the US, multi-vitamin/mineral products typically contain 2 to 4 mg of vitamin B6 per daily serving as pyridoxine hydrochloride. However, many US dietary supplement companies also market a B6-only dietary supplement with 100 mg per daily serving.[1] While theUS National Academy of Medicine set an adult safety UL at 100 mg/day in 1998,[1][4] in 2023 the European Food Safety Authority set its UL at 12 mg/day.[22]
The Japanese Ministry of Health, Labor, and Welfare (MHLW) set up the 'Foods for Specified Health Uses' (特定保健用食品; FOSHU) regulatory system in 1991 to individually approve the statements made on food labels concerning the effects of foods on the human body. The regulatory range of FOSHU was later broadened to allow for the certification of capsules and tablets. In 2001, MHLW enacted a new regulatory system, 'Foods with Health Claims' (保健機能食品; FHC), which consists of the existing FOSHU system and the newly established 'Foods with Nutrient Function Claims' (栄養機能表示食品; FNFC), under which claims were approved for any product containing a specified amount perserving of 12 vitamins, including vitamin B6, and two minerals.[34][35] To make a health claim based on a food's vitamin B6 content, the amount per serving must be in the range of 0.3–25 mg. The allowed claim is: "Vitamin B6 is a nutrient that helps produce energy from protein and helps maintain healthy skin andmucous membranes."[36][37]
In 2010, the European Food Safety Authority (EFSA) published a review of proposed health claims for vitamin B6, disallowing claims for bone, teeth, hair skin and nails, and allowing claims that the vitamin provided for normalhomocysteine metabolism, normal energy-yielding metabolism, normal psychological function, reduced tiredness and fatigue, and provided for normal cysteine synthesis.[38]
The USFood and Drug Administration (FDA) has several processes for permitting health claims on food and dietary supplement labels.[39] There are no FDA-approved Health Claims or Qualified Health Claims for vitamin B6. Structure/Function Claims can be made without FDA review or approval as long as there is some credible supporting science.[39] Examples for this vitamin are "Helps support nervous system function" and "Supports healthy homocysteine metabolism."
Vitamin B6 is absorbed in thejejunum of the small intestine bypassive diffusion.[1][4] Even extremely large amounts are well absorbed. Absorption of the phosphate forms involves their dephosphorylation catalyzed by the enzymealkaline 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 asalvage pathway that requires three key enzymes,pyridoxal kinase,pyridoxine 5'-phosphate oxidase, andphosphatases.[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 ofpyridoxine is up to 20 days,[40] while another source indicates half-life ofvitamin B6 is in range of 25 to 33 days.[41] After considering the different sources, it can be concluded that the half-life of vitamin B6 is typically measured in several weeks.[40][41]
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 ofaldehyde oxidase in the liver. Amounts excreted increase within 1–2 weeks with vitamin supplementation and decrease as rapidly after supplementation ceases.[4][42] 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]
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 thecoenzymepyridoxal 5' phosphate (PLP).[1] The most prominent of the lesions is due to impairedtryptophan–niacin conversion. This can be detected based on urinary excretion ofxanthurenic acid after an oral tryptophan load. Vitamin B6 deficiency can also result in impairedtranssulfuration ofmethionine tocysteine. The PLP-dependent transaminases and glycogen phosphorylase provide the vitamin with its role ingluconeogenesis, so deprivation of vitamin B6 results in impairedglucose tolerance.[1][15]
The assessment of vitamin B6 status is essential, as the clinical signs and symptoms in less severe cases are not specific.[43] 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.[42] 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.[42] Other methods of measurement, includingUV spectrometric,spectrofluorimetric,mass spectrometric,thin-layer andhigh-performance liquid chromatographic,electrophoretic,electrochemical, and enzymatic, have been developed.[42][44]
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.[45]
An overview of the history was published in 2012.[54] In 1934, the Hungarian physicianPaul György discovered a substance that was able to cure a skin disease in rats (dermatitis acrodynia). He named this substance vitamin B6, as numbering of the B vitamins was chronological, andpantothenic acid had been assigned vitamin B5 in 1931.[55][56] In 1938,Richard Kuhn was awarded theNobel Prize in Chemistry for his work on carotenoids and vitamins, specifically B2 and B6.[57] Also in 1938, Samuel Lepkovsky isolated vitamin B6 from rice bran.[54] A year later, Stanton A. Harris andKarl August Folkers determined the structure of pyridoxine and reported success inchemical synthesis,[58] and then in 1942Esmond Emerson Snell developed a microbiological growthassay that led to the characterization of pyridoxamine, the aminated product of pyridoxine, and pyridoxal, theformyl derivative of pyridoxine.[54] Further studies showed that pyridoxal, pyridoxamine, and pyridoxine have largely equal activity in animals and owe their vitamin activity to the ability of the organism to convert them into the enzymatically active form pyridoxal-5-phosphate.[54]
Following a recommendation ofIUPAC-IUB in 1973,[59] vitamin B6 is the official name for all 2-methyl,3-hydroxy,5-hydroxymethylpyridine derivatives exhibiting the biological activity of pyridoxine.[60] Because these related compounds have the same effect, the word "pyridoxine" should not be used as a synonym for vitamin B6.
Observational studies suggested aninverse correlation between a higher intake of vitamin B6 and allcancers, with the strongest evidence for gastrointestinal cancers. However, evidence from a review ofrandomized 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.[61] 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.[62][63][64]
According to a prospectivecohort 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.[65] 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.[66]
Forcoronary heart disease, ameta-analysis reported lower relative risk for a 0.5 mg/day increment in dietary vitamin B6 intake.[67] 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[68] nor treatment[69] showed any significant benefit oncognition anddementia risk. Low dietary vitamin B6 correlated with a higher risk ofdepression in women but not in men.[70] When treatment trials were reviewed, no meaningful treatment effect for depression was reported, but a subset of trials inpre-menopausal women suggested a benefit, with a recommendation that more research was needed.[71] The results of several trials with children diagnosed as havingautism spectrum disorder (ASD) treated with high dose vitamin B6 andmagnesium did not result in treatment effect on the severity of symptoms of ASD.[72]
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