|Use||Vitamin B6 deficiency|
|Biological target||enzyme cofactor|
|Drugs.com||International Drug Names|
Vitamin B6 refers to a group of chemically similar compounds which can be interconverted in biological systems. Vitamin B6 is part of the vitamin B group of essential nutrients. Its active form, pyridoxal 5′-phosphate, serves as a coenzyme in some 100 enzyme reactions in amino acid, glucose, and lipid metabolism.
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 produced from riboflavin (vitamin B2).
- Pyridoxine (PN), the form most commonly given as vitamin B6 supplement
- Pyridoxine 5′-phosphate (P5P)
- Pyridoxal (PL)
- Pyridoxal 5′-phosphate (PLP), the metabolically active form
- Pyridoxamine (PM)
- Pyridoxamine 5′-phosphate (PMP)
- 4-Pyridoxic acid, the catabolite which is excreted in urine
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
- 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 d-serine from its enantiomer is a PLP-dependent enzyme.
- PLP is a coenzyme needed for the proper function of the enzymes cystathionine synthase and cystathionase. These enzymes catalyze reactions in the catabolism of methionine. Part of this pathway (the reaction catalyzed by cystathionase) also produces 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 impairs this conversion.
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.
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 sphingosine-1-phosphate lyase, the enzyme responsible for breaking down sphingosine-1-phosphate, is also PLP-dependent.
Hemoglobin synthesis and function
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.
Vitamin B6 is widely distributed in foods in both its free and bound forms. 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 30–70% 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. The heating that occurs before most freezing and canning processes may also result in the loss of vitamin B6 in foods.
- fortified breakfast cereals
- dark chocolate
The U.S. Institute of Medicine (renamed National Academy of Medicine in 2015) updated Estimated Average Requirements (EARs) and Recommended Dietary Allowances (RDAs) for vitamin B6 in 1998. EARs for vitamin B6 for women and men ages 14 and up increase with age from 1.0 to 1.3 mg/day and from 1.1 to 1.4 mg/day, respectively; the RDAs increase with age from 1.2 to 1.5 and from 1.3 to 1.7 mg/day, respectively. RDAs are higher than EARs so as to identify amounts that will cover people with higher than average requirements. RDA for pregnancy is 1.9 mg/day. RDA for lactation is 2.0 mg/day. For infants up to 12 months the Adequate Intake (AI) is 0.1–0.3 mg/day. and for children ages 1–13 years the RDA increases with age from 0.5 to 1.0 mg/day. As for safety, Tolerable upper intake levels (ULs) for vitamins and minerals are identified when evidence is sufficient. In the case of vitamin B6 the UL is set at 100 mg/day. Collectively the EARs, RDAs, AIs and ULs are referred to as Dietary Reference Intakes (DRIs).
The European Food Safety Authority (EFSA) refers to the collective set of information as Dietary Reference Values, with Population Reference Intake (PRI) instead of RDA, and Average Requirement instead of EAR. AI and UL defined the same as in United States. For women and men ages 15 and older the PRI is set at 1.6 and 1.7 mg/day, respectively. AI for pregnancy is 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. These PRIs are slightly higher than the U.S. RDAs. The EFSA also reviewed the safety question and set its UL at 25 mg/day.
For U.S. food and dietary supplement labeling purposes the amount in a serving is expressed as a percent of Daily Value (%DV). 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 RDA. A table of the old and new adult Daily Values is provided at Reference Daily Intake. Large food and supplement companies have until January 1, 2020 to comply with the change, small companies until 1 January 2021.
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 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 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.
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 sphingosine synthesis) and sideroblastic anemia (due to impaired heme synthesis).
Less severe cases present with metabolic disease associated with insufficient activity 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.
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 10 nmol/l is indicative of vitamin B6 deficiency. 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. 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.
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. Overconsumption of seeds from Ginkgo biloba can deplete vitamin B6.
Adverse effects have been documented from vitamin B6 supplements, but never from food sources. Damage to the dorsal root ganglia 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 dietary upper limit (UL) over long periods cause 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.
Existing authorizations and valuations vary considerably worldwide. As noted, the U.S. Institute of Medicine set an adult UL at 100 mg/day. The European Community Scientific Committee on Food defined intakes of 50 mg of vitamin B6 per day as harmful and established a UL of 25 mg/day. The nutrient reference values in Australia and New Zealand recommend an upper limit of 50 mg/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 1 g/day. "A no-observed-adverse-effect level (NOAEL) 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."
In 1934, the Hungarian physician Paul György discovered a substance that was able to cure a skin disease in rats (dermatitis 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.
- "Vitamin B6". Micronutrient Information Center, Linus Pauling Institute, Oregon State University, Corvallis, OR. May 2014. Archived from the original on 2018-03-14. Retrieved 7 March 2017.
- Ink SL, Henderson LM (1984). "Vitamin B6 metabolism". Annual Review of Nutrition. 4: 455–70. doi:10.1146/annurev.nu.04.070184.002323. PMID 6380540.
- Johansson S, Lindstedt S, Tiselius HG (October 1974). "Metabolic interconversions of different forms of vitamin B6". The Journal of Biological Chemistry. 249 (19): 6040–6. PMID 4418204.
- Combs GF (2007). The Vitamins: Fundamental Aspects in Nutrition and Health (3rd ed.). San Diego: Elsevier Academic Press. pp. 320–324. ISBN 978-0-8121-0661-9. LCCN 2007026776. OCLC 150255807.
- Lichtstein HC, Gunsalus IC, Umbreit WW (1945). "Function of the vitamin B6 group; pyridoxal phosphate (codecarboxylase) in transamination" (PDF). The Journal of Biological Chemistry. 161 (1): 311–20. PMID 21005738.
- Erskine PT, Coates L, Butler D, Youell JH, Brindley AA, Wood SP, et al. (August 2003). "X-ray structure of a putative reaction intermediate of 5-aminolaevulinic acid dehydratase". The Biochemical Journal. 373 (Pt 3): 733–8. doi:10.1042/bj20030513. PMC 1223560. PMID 12777167.
- McCormick DB (2006). "Vitamin B6". In Bowman BA, Russell RM (eds.). Present Knowledge in Nutrition. 2 (9th ed.). Washington, DC: International Life Sciences Institute. pp. 270, 273. ISBN 978-1-57881-199-1. LCCN 2006285949. OCLC 726187692.
- Sauberlich HE (1987). "Vitamins – how much is for keeps?". Nutrition Today. 22: 20–28. doi:10.1097/00017285-198701000-00004.
- "B vitamins and folic acid". nhs.uk. Retrieved 2018-10-23.
- "10973, Pork, ground, 96% lean / 4% fat, raw". National Nutrient Database for Standard Reference, Release 27. United States Department of Agriculture, Agricultural Research Service. Retrieved 27 June 2015.
- "05305, Ground turkey, raw". National Nutrient Database for Standard Reference, Release 27. United States Department of Agriculture, Agricultural Research Service. Retrieved 27 June 2015.
- "23040, Beef, chuck, shoulder clod, shoulder top and center steaks, separable lean and fat, trimmed to 0" fat, select, cooked, grilled". National Nutrient Database for Standard Reference, Release 27. United States Department of Agriculture, Agricultural Research Service. Retrieved 27 June 2015.
- "09040, Bananas, raw". National Nutrient Database for Standard Reference, Release 27. United States Department of Agriculture, Agricultural Research Service. Retrieved 27 June 2015.
- "16360, Chickpeas (garbanzo beans, bengal gram), mature seeds, canned, solids and liquids, low sodium". National Nutrient Database for Standard Reference, Release 27. United States Department of Agriculture, Agricultural Research Service. Retrieved 27 June 2015.
- ", FoodData Central Search Results".
- "11356, Potatoes, Russet, flesh and skin, baked". National Nutrient Database for Standard Reference, Release 27. United States Department of Agriculture, Agricultural Research Service. Retrieved 27 June 2015.
- "12151, Nuts, pistachio nuts, raw". National Nutrient Database for Standard Reference, Release 27. United States Department of Agriculture, Agricultural Research Service. Retrieved 27 June 2015.
- Institute of Medicine (1998). "Vitamin B6". Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: The National Academies Press. pp. 150–195. doi:10.17226/6015. ISBN 978-0-309-06554-2. LCCN 00028380. OCLC 475527045. PMID 23193625.
- "Overview on Dietary Reference Values for the EU population as derived by the EFSA Panel on Dietetic Products, Nutrition and Allergies" (PDF). 2017. Archived (PDF) from the original on 2017-08-28.
- "Tolerable Upper Intake Levels For Vitamins And Minerals" (PDF). European Food Safety Authority. 2006. Archived (PDF) from the original on 2017-09-19.
- "Federal Register May 27, 2016 Food Labeling: Revision of the Nutrition and Supplement Facts Labels" (PDF). Archived (PDF) from the original on 2017-09-22.
- Nutrition, Center for Food Safety and Applied. "Labeling & Nutrition - Changes to the Nutrition Facts Label". www.fda.gov. Archived from the original on 2018-04-18. Retrieved 2018-04-20.
- Andrews' Diseases of the Skin (10th ed.). Elsevier.
- Gibson RS (2005). "Assessment of vitamin B6 status". Principles of Nutritional Assessment (2nd ed.). New York: Oxford University Press. pp. 575–594. ISBN 978-0-19-517169-3. LCCN 2004054778. OCLC 884490740.
- Lui A, Lumeng L, Aronoff GR, Li TK (November 1985). "Relationship between body store of vitamin B6 and plasma pyridoxal-P clearance: metabolic balance studies in humans". The Journal of Laboratory and Clinical Medicine. 106 (5): 491–7. PMID 4056565.
- Leklem JE (November 1990). "Vitamin B-6: a status report". The Journal of Nutrition. 120 Suppl 11 (4): 1503–7. doi:10.1093/jn/120.suppl_11.1503. PMID 2243296.
- Menkes JH (1980). Textbook of Child Neurology (2nd ed.). Philadelphia: Henry Kimpton Publishers. p. 486. ISBN 978-0-8121-0661-9. LCCN 79010975. OCLC 925196268.
- Massé PG, Boudreau J, Tranchant CC, Ouellette R, Ericson KL (February 2012). "Type 1 diabetes impairs vitamin B(6) metabolism at an early stage of women's adulthood". Applied Physiology, Nutrition, and Metabolism. 37 (1): 167–75. doi:10.1139/h11-146. PMID 22288928.
- Ulvik A, Midttun Ø, Pedersen ER, Eussen SJ, Nygård O, Ueland PM (July 2014). "Evidence for increased catabolism of vitamin B-6 during systemic inflammation". The American Journal of Clinical Nutrition. 100 (1): 250–5. doi:10.3945/ajcn.114.083196. PMID 24808485.
- Rall LC, Meydani SN (August 1993). "Vitamin B6 and immune competence". Nutrition Reviews. 51 (8): 217–25. doi:10.1111/j.1753-4887.1993.tb03109.x. PMID 8302491.
- Bhagavan HN (1985). "Interaction between vitamin B6 and drugs". In Reynolds RD, Leklem JE (eds.). Vitamin B6: Its Role in Health and Disease. New York: Liss. pp. 401–415.
- Wilson SM, Bivins BN, Russell KA, Bailey LB (October 2011). "Oral contraceptive use: impact on folate, vitamin B₆, and vitamin B₁₂ status". Nutrition Reviews. 69 (10): 572–83. doi:10.1111/j.1753-4887.2011.00419.x. PMID 21967158.
- Schwaninger M, Ringleb P, Winter R, Kohl B, Fiehn W, Rieser PA, Walter-Sack I (March 1999). "Elevated plasma concentrations of homocysteine in antiepileptic drug treatment". Epilepsia. 40 (3): 345–50. doi:10.1111/j.1528-1157.1999.tb00716.x. PMID 10080517.
- Corken M, Porter J (September 2011). "Is vitamin B(6) deficiency an under-recognized risk in patients receiving haemodialysis? A systematic review: 2000-2010". Nephrology. 16 (7): 619–25. doi:10.1111/j.1440-1797.2011.01479.x. PMID 21609363.
- Kobayashi, Daisuke (2019). "Food poisoning by Ginkgo seeds through vitamin B6 depletion (article in Japanese)". Yakugaku Zasshi. 139 (1): 1–6. doi:10.1248/yakushi.18-00136. ISSN 0031-6903. PMID 30606915.
- Wada, Keiji; Ishigaki, Seikou; Ueda, Kaori; Sakata, Masakatsu; Haga, Masanobu (1985). "An antivitamin B6, 4'-methoxypyridoxine, from the seed of Ginkgo biloba L.". Chemical & Pharmaceutical Bulletin. 33 (8): 3555–3557. doi:10.1248/cpb.33.3555. ISSN 0009-2363. PMID 4085085.
- Schaumburg H, Kaplan J, Windebank A, Vick N, Rasmus S, Pleasure D, Brown MJ (August 1983). "Sensory neuropathy from pyridoxine abuse. A new megavitamin syndrome". The New England Journal of Medicine. 309 (8): 445–8. doi:10.1056/NEJM198308253090801. PMID 6308447.
- Foca FJ (September 1985). "Motor and sensory neuropathy secondary to excessive pyridoxine ingestion". Archives of Physical Medicine and Rehabilitation. 66 (9): 634–6. PMID 2994596.
- Katan MB (November 2005). "[How much vitamin B6 is toxic?]". Nederlands Tijdschrift voor Geneeskunde. 149 (46): 2545–6. PMID 16320662.
- Dalton K, Dalton MJ (July 1987). "Characteristics of pyridoxine overdose neuropathy syndrome". Acta Neurologica Scandinavica. 76 (1): 8–11. doi:10.1111/j.1600-0404.1987.tb03536.x. PMID 3630649.
- Scientific Panel on Food Additives, Flavourings, Processing Aids and Materials in Contact with Food (2008). "Opinion on Pyridoxal 5′-phosphate as a source for vitamin B6 added for nutritional purposes in food supplements". The EFSA Journal. 760: 1–13. doi:10.2903/j.efsa.2008.760.CS1 maint: multiple names: authors list (link)
- Berger A, Schaumburg HH (October 1984). "More on neuropathy from pyridoxine abuse". The New England Journal of Medicine. 311 (15): 986–7. doi:10.1056/NEJM198410113111513. PMID 6472428.
- Dalton K (May 1985). "Pyridoxine overdose in premenstrual syndrome". Lancet. 1 (8438): 1168–9. doi:10.1016/S0140-6736(85)92480-8. PMID 2860378.
- Del Tredici AM, Bernstein AL, Chinn K (1985). "Carpal tunnel syndrome and vitamin B6 therapy.". In Reynolds RD, Leklem JE (eds.). Vitamin B6: Its Role in Health and Disease. New York: Liss. pp. 459–462.
- Parry GJ, Bredesen DE (October 1985). "Sensory neuropathy with low-dose pyridoxine". Neurology. 35 (10): 1466–8. doi:10.1212/WNL.35.10.1466. PMID 2993949.
- "Vitamin B6". www.nrv.gov.au. 2014-03-17. Archived from the original on 2018-03-13. Retrieved 2018-04-20.
- György P (1934). "Vitamin B2 and the Pellagra-like Dermatitis in Rats". Nature. 133 (3361): 498–9. doi:10.1038/133498a0.
- György P, Eckardt RE (September 1940). "Further investigations on vitamin B(6) and related factors of the vitamin B(2) complex in rats. Parts I and II". The Biochemical Journal. 34 (8–9): 1143–54. doi:10.1042/bj0341143. PMC 1265394. PMID 16747297.
- 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)