Vitamin B6 (Pyridoxine) is a water-soluble substance that is converted inside the body into essential coenzymes for more than 100 enzymes in the human body.
Vitamin B6 has three natural forms: pyridoxine (PN), pyridoxal (PL), and pyridoxamine (PM), all of which transform into its active forms in the body, which is the coenzyme pyridoxal 5-phosphate (PLP or P5P).
PLP, the functioning structure in the body, mainly serves as a coenzyme in amino acid, protein, carbohydrate, and lipid metabolism, in addition to neurotransmitter synthesis. It is also involved in glycogenolysis and gluconeogenesis.
There are only two FDA-approved drugs containing pyridoxine or its analogs; the first is a combination of several vitamins including B6 indicated for the prevention of vitamin deficiency in pediatric and adult patients receiving parenteral nutrition, and the second is a combination of doxylamine succinate and pyridoxine hydrochloride (a vitamin B6 analog) in oral tablet form for treatment of nausea and vomiting of pregnancy that does not respond to conservative management.
Vitamin B6 is indicated in cases of its deficiency, which may be due to poor renal function, autoimmune diseases, increased alcohol intake, or isoniazid, cycloserine, valproic acid, phenytoin, carbamazepine, primidone, hydralazine, and theophylline therapy. Inadequate vitamin B6 intake is a rare cause of its deficiency.
Vitamin B6 deficiency can be observed clinically as seborrheic dermatitis, microcytic anemia, dental decay, glossitis, epileptiform convulsions, peripheral neuropathy, electroencephalographic abnormalities, depression, confusion, and weakened immune function.
Some rare inborn errors of metabolism result from defects in the coenzyme binding sites of the responsible enzymes where PLP is attached, and administering very high doses of vitamin B6 is crucial for the functioning of these enzymes. These disorders are called vitamin B6 dependency syndromes. Examples of these syndromes are: convulsions of the newborn, xanthurenic aciduria, cystathioninuria, primary hyperoxaluria, homocystinuria, sideroblastic anemia and gyrate atrophy with ornithinuria.
Furthermore, some toxicological uses of pyridoxine include isoniazid overdose, false morel (gyromitra) mushroom poisoning, hydrazine exposure, ethylene glycol toxicity, and crimidin toxicity.
There is some proof of Vitamin B6 being effective in suppression of lactation as well as in relieving side effects of oral contraceptives such as depression and nausea.
Research has found conflicting results regarding the use of vitamin B6 supplements in treating gestational diabetes, premenstrual syndrome, carpal tunnel syndrome, morning sickness, and in treating and preventing essential hypertension.
Even though scant evidence regarding pyridoxine’s efficacy exists regarding these uses, it has been used empirically in the treatment of some conditions including atopic dermatitis, dental caries, acute alcohol intoxication, autism, diabetic complications, Down syndrome, schizophrenia, Huntington chorea, and steroid-dependent asthma..
PLP catalyzes different reactions such as transamination, decarboxylation, racemization, and elimination, in either enzyme-bound or free form. These reactions are significantly facilitated and accelerated in the presence of PLP due to the electron-withdrawing nature of the molecule, which unstabilizes the bonds around the alpha-carbon atom through the system formed with amino acids.
Metabolism of Vitamin B6
Pyridoxine, pyridoxamine, and pyridoxal are rapidly absorbed from food and oral drugs by mucosal cells of the small intestine, while their phosphorylated analogs first undergo dephosphorylation and are then absorbed.
After their uptake, PM and PN are acted on by PL kinase to form PMP and PNP respectively; then, these compounds are converted by pyridoxine (pyridoxamine) phosphate (PNP) oxidase enzyme into the coenzyme PLP. This process only occurs in hepatocytes, and to a lesser extent, in mucosal cells of the small intestine, due to a lack of PNP oxidase in most tissues. Due to cell membranes being impermeable to PLP, it is either dephosphorylated by phosphohydrolase enzyme so that PL can be released into the bloodstream, or is directly attached to albumin and liberated by the hepatocytes into the circulation as PLP-albumin complex. PLP is also uptaken by erythrocytes and carried by hemoglobin to other tissues.
Finally, protein-bound PLP is dephosphorylated, and the end-product PL in combination with the free PL in plasma is then transformed inside target tissues by the effect of pyridoxal kinase enzyme into the coenzyme PLP which is the active form of vitamin B6. PLP is bound to various proteins inside tissues to protect it from phosphatase enzymes.
The administration of vitamin B6 can be both via oral and intravenous routes. Oral vitamin B6 is the most prevalent form available, while the intravenous form is useful in some special cases, such as malabsorption syndromes, anorexia, and in patients on parenteral nutrition. It is also present in intramuscular and subcutaneous forms.
The most known adverse effect of vitamin B6 supplementation is sensory neuropathy, but this pathology rarely occurs below toxic doses–which is 1 gm/day or more for adults–and there is no evidence of its occurrence in doses lower than 100 mg/day for less than 30 weeks in adults. It is worth noting that the average dietary requirement of vitamin B6 for adults is 1.75 mg/day.
There are no reported adverse effects caused by dietary concentrations nor by regular supplemental doses of vitamin B6, while higher doses below levels of toxicity may cause indigestion, nausea, breast tenderness, photosensitivity, and vesicular dermatoses.
The only two contraindications for vitamin B6 are hypervitaminosis B6; as toxic levels may cause sensory neuropathy, and hypersensitivity to pyridoxine.
The therapeutic index of B6 is variable between individuals as individual susceptibility to toxic adverse effects is noted, but some studies state a cutoff value of 100 grams over 20 months, below which toxicity-related neuropathy does not occur.
Vitamin B6 is highly absorbable from food and drugs, and high concentrations can be rapidly reached, however, the human body excretes the excess in urine as 4-pyridoxic acid, and it is also excreted unchanged when taking very high doses. Monitoring of the amount of vitamin B6 in the body is for three reasons; to confirm depletion or toxicity and in research studies concerned with vitamin B6.
Vitamin B6 monitoring divides into direct and functional methods. The direct methods are through measuring the concentration of the vitamin in plasma, blood cells, or urine. Plasma PLP concentration is the best monitoring method as it reflects B6 stores in the entire body.
The functional methods, such as tryptophan load test, plasma homocysteine levels, and blood transaminase activity, are also used in detecting B6 deficiency. Erythrocyte aspartate aminotransferase and alanine aminotransferase stimulation tests can evaluate long term vitamin B6 status, and their values increase with B6 depletion.
Vitamin B6 can be toxic if its concentration in the body is too high, causing sensory neuropathy, whose mechanism is unknown. The degeneration of sensory fibers of peripheral nerves and its myelin and also the dorsal columns of the spinal cord cause bilateral loss of peripheral sensation or hyperaesthesia, accompanied by limb pain, ataxia, and loss of balance. The condition regresses gradually after cessation of taking the supplement till regaining normal activity. Higher doses can cause testicular atrophy and reduced sperm motility.
Research on the subject found that the duration of administration of the vitamin is directly proportional to the risk of clinically-evident toxicity with respect to the total dose given.
Adequate nutrition is essential for any vitamin prevention. Healthcare professionals should advise consuming vitamin B6-rich foods such as chickpea, liver, poultry, and fortified ready-to-eat cereals. B6 deficiency is generally rare due to dietary inadequacy.
Gynecologists, obstetricians, neurologists, hematologists, and dermatologists often need to diagnose, treat, and collaborate about patients with Vitamin B6 deficiency or excess. The clinical picture accompanying vitamin B6 deficiency is not characteristic to it, so thorough analysis and good observation skills are needed to identify the problem. Susceptible populations, such as patients with chronic diseases and poor quality diet, should be identified and managed accordingly.
Clinical use of vitamin B6 in some diseases is controversial, as no definite evidence is available for its use in those conditions. But because of the relative safety of high doses of water-soluble vitamins, no strict monitoring of the patients is needed. Some conditions require much higher doses than normally necessary, such as dependency syndromes, and observation for adverse effects is necessary.
|||SNELL EE, Chemical structure in relation to biological activities of vitamin B6. Vitamins and hormones. 1958; [PubMed PMID: 13625598]|
|||RABINOWITZ JC,SNELL EE, The vitamin B6 group; microbiological and natural occurrence of pyridoxamine phosphate. The Journal of biological chemistry. 1947 Aug; [PubMed PMID: 20259097]|
|||SNELL EE, Summary of known metabolic functions of nicotinic acid, riboflavin and vitamin B6. Physiological reviews. 1953 Oct; [PubMed PMID: 13100067]|
|||Ebadi M, Regulation and function of pyridoxal phosphate in CNS. Neurochemistry international. 1981; [PubMed PMID: 19643063]|
|||Wibowo N,Purwosunu Y,Sekizawa A,Farina A,Tambunan V,Bardosono S, Vitamin B₆ supplementation in pregnant women with nausea and vomiting. International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics. 2012 Mar; [PubMed PMID: 22189065]|
|||Matthews A,Haas DM,O'Mathúna DP,Dowswell T,Doyle M, Interventions for nausea and vomiting in early pregnancy. The Cochrane database of systematic reviews. 2014 Mar 21; [PubMed PMID: 24659261]|
|||Vech RL,Lumeng L,Li TK, Vitamin B6 metabolism in chronic alcohol abuse The effect of ethanol oxidation on hepatic pyridoxal 5'-phosphate metabolism. The Journal of clinical investigation. 1975 May; [PubMed PMID: 1168205]|
|||Snider DE Jr, Pyridoxine supplementation during isoniazid therapy. Tubercle. 1980 Dec; [PubMed PMID: 6269259]|
|||Raskin NH,Fishman RA, Pyridoxine-deficiency neuropathy due to hydralazine. The New England journal of medicine. 1965 Nov 25; [PubMed PMID: 5847557]|
|||Nair S,Maguire W,Baron H,Imbruce R, The effect of cycloserine on pyridoxine-dependent metabolism in tuberculosis. Journal of clinical pharmacology. 1976 Aug-Sep; [PubMed PMID: 972198]|
|||Clayton PT, B6-responsive disorders: a model of vitamin dependency. Journal of inherited metabolic disease. 2006 Apr-Jun; [PubMed PMID: 16763894]|
|||Apeland T,Frøyland ES,Kristensen O,Strandjord RE,Mansoor MA, Drug-induced pertubation of the aminothiol redox-status in patients with epilepsy: improvement by B-vitamins. Epilepsy research. 2008 Nov; [PubMed PMID: 18644700]|
|||Lheureux P,Penaloza A,Gris M, Pyridoxine in clinical toxicology: a review. European journal of emergency medicine : official journal of the European Society for Emergency Medicine. 2005 Apr; [PubMed PMID: 15756083]|
|||MUELLER JF,VILTER RW, Pyridoxine deficiency in human beings induced with desoxypyridoxine. The Journal of clinical investigation. 1950 Feb; [PubMed PMID: 15403983]|
|||Hawkins WW,Barsky J, An Experiment on Human Vitamin B6 Deprivation. Science (New York, N.Y.). 1948 Sep 10; [PubMed PMID: 17842719]|
|||Salam RA,Zuberi NF,Bhutta ZA, Pyridoxine (vitamin B6) supplementation during pregnancy or labour for maternal and neonatal outcomes. The Cochrane database of systematic reviews. 2015 Jun 3; [PubMed PMID: 26039815]|
|||Riikonen R,Mankinen K,Gaily E, Long-term outcome in pyridoxine-responsive infantile epilepsy. European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society. 2015 Nov; [PubMed PMID: 26310861]|
|||Frimpter GW,Andelman RJ,George WF, Vitamin B6-dependency syndromes. New horizons in nutrition. The American journal of clinical nutrition. 1969 Jun; [PubMed PMID: 4892594]|
|||Bender DA, Non-nutritional uses of vitamin B6. The British journal of nutrition. 1999 Jan; [PubMed PMID: 10341670]|
|||Bendich A,Cohen M, Vitamin B6 safety issues. Annals of the New York Academy of Sciences. 1990; [PubMed PMID: 2192616]|
|||Larsson SC,Orsini N,Wolk A, Vitamin B6 and risk of colorectal cancer: a meta-analysis of prospective studies. JAMA. 2010 Mar 17; [PubMed PMID: 20233826]|
|||Tryfiates GP, Effects of pyridoxine on serum protein expression in hepatoma-bearing rats. Journal of the National Cancer Institute. 1981 Feb; [PubMed PMID: 6935482]|
|||Hayashi H,Wada H,Yoshimura T,Esaki N,Soda K, Recent topics in pyridoxal 5'-phosphate enzyme studies. Annual review of biochemistry. 1990; [PubMed PMID: 2197992]|
|||Hamm MW,Mehansho H,Henderson LM, Transport and metabolism of pyridoxamine and pyridoxamine phosphate in the small intestine of the rat. The Journal of nutrition. 1979 Sep; [PubMed PMID: 479950]|
|||Buss DD,Hamm MW,Mehansho H,Henderson LM, Transport and metabolism of pyridoxine in the perfused small intestine and the hind limb of the rat. The Journal of nutrition. 1980 Aug; [PubMed PMID: 7400856]|
|||Tsuji T,Yamada R,Nose Y, Intestinal absorption of vitamin B6. I. Pyridoxol uptake by rat intestinal tissue. Journal of nutritional science and vitaminology. 1973 Oct; [PubMed PMID: 4792211]|
|||Mehansho H,Buss DD,Hamm MW,Henderson LM, Transport and metabolism of pyridoxine in rat liver. Biochimica et biophysica acta. 1980 Aug 1; [PubMed PMID: 7397240]|
|||Mehansho H,Henderson LM, Transport and accumulation of pyridoxine and pyridoxal by erythrocytes. The Journal of biological chemistry. 1980 Dec 25; [PubMed PMID: 7440576]|
|||Li TK,Lumeng L,Veitch RL, Regulation of pyridoxal 5'-phosphate metabolism in liver. Biochemical and biophysical research communications. 1974 Nov 27; [PubMed PMID: 4375996]|
|||Sensory neuropathy from pyridoxine abuse. The New England journal of medicine. 1984 Jan 19; [PubMed PMID: 6318110]|
|||Ink SL,Henderson LM, Vitamin B6 metabolism. Annual review of nutrition. 1984; [PubMed PMID: 6380540]|
|||Ueland PM,Ulvik A,Rios-Avila L,Midttun Ø,Gregory JF, Direct and Functional Biomarkers of Vitamin B6 Status. Annual review of nutrition. 2015; [PubMed PMID: 25974692]|
|||Tsutsumi S,Tanaka T,Gotoh K,Akaike M, Effects of pyridoxine on male fertility. The Journal of toxicological sciences. 1995 Aug; [PubMed PMID: 8667459]|