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Sources and physiological effects

Dietary sources
Vitamin B₆ refers to a group of different pyridine derivatives that can be converted into each other. These compounds are almost ubiquitous in the animal and plant world, even if only in small quantities. While pyridoxal and pyridoxamine are mainly found in animal sources, foods of plant origin mainly provide pyridoxine. Meat, fish, wholemeal products, pods, nuts and potatoes are considered rich sources of vitamin B₆. Due to the processing and preparation of food, the vitamin B6 content of the diet can sometimes drop considerably. In the production of white flour vitamin B₆ content of the grain is reduced by 85%. During storage and food preparation, water solubility (leaching) and light sensitivity are particularly important. For example, a 2-hour exposure to the sun halves the vitamin B₆ content of milk in a clear glass bottle. The heat stability of vitamin B₆ depends on the compound it contains. Plant foods containing (mainly) pyridoxine are less sensitive to heat than animal foods containing (mainly) pyridoxal or pyridoxamine.
Physiological effects
Homocysteine metabolism	Degradation of homocysteine to cysteine and L-glutathione
Fat/carbohydrate metabolism	Stimulation of gluconeogenesis
Protein/amino acid metabolism	Biosynthesis of neurotransmitters such as serotonin, norepinephrine, dopamine, GABA
Blood	Hemosynthesis and erythrocyte maturation
Immune system	Regulation of lymphocyte and antibody proliferation

EFSA Health Claims

Health claims		EFSA opinion
Vitamin B₆ (pyridoxine)	Contributes to normal cysteine synthesis Contributes to a normal energy metabolism Contributes to a normal homocysteine metabolism Contributes to normal psychological function Contributes to the reduction of fatigue Contributes to a normal function of the nervous system Contributes to protein and glycogen metabolism Contributes to the normal formation of red blood cells Contributes to a normal function of the immune system Contributes to the regulation of hormone activity

Recommended intake

D-A-CH recommended nutrient intake (Reference values EFSA and NHI )
	Age	Vitamin B₆(mg/d)
Infants (months)
	0-4	0.1
	4-12	0.3
Children (years)
	1-4	0.6
	4-7	0.7
	7-10	1.0
	10-13	1.2
	13-15	1.4
Teenagers/adults (years)		Women	Men
	15-19	1.6	1.4
	19-25	1.6	1.4
	25-51	1.6	1.4
	51-65	1.6	1.4
	> 65	1.6	1.4
Pregnancy	1.8
Breast-feeding	1.6
Increased need	Growth, pregnancy, weight training, high protein diet, alcohol abuse, smoking, chronic diseases such as diabetes mellitus, renal insufficiency, bronchial asthma, tryptophan metabolism disorders etc.
Special groups at risk of deficiency	Weightlifters, chronically ill people

Recommended intake according to food labelling regulations		Vitamin B₆
(=100 % TB marking on label)		1.4 mg
Nutrient safety
UL	Long-term daily intake, where no adverse health effects are expected	100 mg/d (according to NIH)
NOAEL	Maximum uptake dose, with no observed adverse effect.	200 mg/d
Safety	European Commission has looked at the safety of Vitamin B₆

Detailed information

Vitamin B₆ and nerve metabolism

Vitamin B₆ is closely linked to amino acid metabolism and is an important factor for neurotransmitter synthesis. As a result, the symptoms of deficiency first appear in the area of nerve metabolism. Non-specific disorders of the central nervous system, increased excitability or nervousness are the first signs of a suboptimal vitamin B₆ supply, which can be treated by vitamin B₆ supplementation (1). Other signs of B₆ deficiency are cramps, impaired movement, paralysis, growth disorders, dermatitis and changes in the mucous membranes (2).

Vitamin B₆ in neurological disorders

Psychological and neurological deficits based on noradrenaline- and dopamine-dependent neurotransmission disorders can be improved by vitamin B₆-supplementation (3). The synthesis of serotonin has a positive effect on insomnia, nervousness and anxiety. A typical sign of vitamin B₆ deficiency is a lack of dream recall (4). In neuropathies and neurological disorders, good outcomes have been observed with high doses of vitamin B₆. In the treatment of carpal tunnel syndrome, an acute to chronic neuropathy in the hand area, vitamin B₆ is considered an efficient, risk-free therapeutic (5).

Vitamin B₆ for PMS

High doses of vitamin B₆ are used for painful menstrual bleeding (dysmenorrhea) and depressive disorders in the premenstrual phase. In several clinical studies, vitamin B₆ supplementation of up to 100 mg/day positively influenced both PMS and premenstrual depression (6). The effectiveness of vitamin B₆ therapy in hormone-dependent depression in premenopausal women has also been demonstrated in several clinical studies (7).

Oral contraceptives affect the B₆-status

It is known that the vitamin B₆ status of oral contraceptives users is significantly lower than those of non-users (8). The large-scale NHANES study conducted in the US in 2003-2004 shows that 75% of users of oral contraceptives who did not additionally supplement had significantly reduced B₆ values (< 20 nmol/l plasma P5P) (9).
Nervousness, irritability and depression are often observed when oral contraceptives are used. There is an established physiological relationship with vitamin-B6 status: Vitamin B₆ is a cofactor in the decarboxylation of amino acids that lead to the formation of neurotransmitters. An estrogen-induced vitamin B₆ deficiency can lead to disorders in tryptophan metabolism and negatively affect serotonin availability in the central nervous system, whereby the symptoms mentioned can manifest themselves (8) (9). Vitamin B₆ deficit seems to be more common in women than previously thought. Micronutrient screening in an Austrian GP's practice showed that 45 % of the women examined had a vitamin B₆ status below the reference range (as opposed to 23 % in men) (10).

Vitamin B₆-Status as a factor of women's health

Insufficient (suboptimal) vitamin B₆ status has short-term and long-term health relevance for users of oral contraceptives. A suboptimal status can trigger complex metabolic disorders that are co-factors for other diseases. For example, new epidemiological studies suggest a negative correlation between vitamin B₆ intake (and folic acid intake) and breast cancer risk (11).

Vitamin B₆ status is also important for later pregnancy. The need for this vitamin increases by 60% during pregnancy due to the increased protein turnover. This increased demand is often not covered by the diet, which is why it is necessary to use the bodies stores. Lower vitamin B₆ values at the beginning of pregnancy increase the risk of a manifest vitamin B₆ deficiency. Vitamin B₆ deficiency leads to an increased risk of premature birth and a lower birth weight (2).

Furthermore, vitamin B₆ together with folic acid and vitamin B₁₂ are involved in the breakdown of the amino acid metabolite homocysteine, which has toxic effects on the endothelium even in low concentrations. Increased homocysteine levels are considered an independent risk factor for atherosclerotic diseases (12) (13).

Homocysteine as a risk factor

Homocysteine is produced by the body from the amino acid methionine. Vitamins B₆, B₁₂ and folic acid are required for the further degradation of homocysteine to cysteine or for the reconstruction to methionine. In hyperhomocysteinemia, these break-down and reconstruction mechanisms are disturbed, which causes homocysteine to accumulate in the plasma. It is well established that increased homocysteine levels pose an independent health risk. The results of the Framingham cohort study show that increased homocysteine levels are associated with an increased risk of cardiovascular disease, stroke, heart failure, dementia and bone fragility (14). Approximately 10% of atherosclerotic diseases are caused by moderate hyperhomocysteinemia and 40% of patients with vascular diseases have elevated levels (15). The homocysteine level is a risk factor that can be influenced by diet and can be reduced by supplementation with folic acid, vitamin B₁₂ and vitamin B₆.

Vitamin B₆-deficiency in old age

In older age, an often poor vitamin B₆ status is associated with a weakening of the immune system, especially with reduced lymphocyte proliferation and interleukin-2 synthesis. The same applies to chronic alcohol consumption. To optimize immune function in these cases, higher pharmacological amounts of vitamin B₆ are necessary (2). Studies also show that patients with rheumatoid arthritis have subnormal vitamin B₆ status. Although substitution cannot suppress the inflammatory processes, there seems to be an increased B₆ need (16), which in turn can lead to a deficiency supply with the symptoms mentioned.

Via the enzyme lysyloxidase, vitamin B₆ is involved in the cross-linking of collagen and elastin. In addition, it modulates the hormone metabolism (12) via interaction with steroid hormone receptors and thus the hormonal skin aging.

Vitamin B₆ and the immune system

The relationship between a suboptimal vitamin B₆ status and a weakened immune system is explained by reduced lymphocyte proliferation and interleukin-2 synthesis. Clinical studies confirm this. For example, vitamin B₆-supplementation of 50 and 100 mg over 14 days significantly increased T-lymphocyte, T-helper cell and total leukocyte levels in critically ill patients (17).

Pyridoxine – a critical nutrient in alcohol disorders

Chronic alcohol consumption affects the metabolism of almost all vitamins. The vitamin B₆ metabolism seems to be particularly affected, because alcohol impairs the phosphorylation of pyridoxine to P5P in the liver. Due to the involvement of P5P in neurotransmitter synthesis, there is a direct correlation with neurological deficits in alcoholics (2). The limited immune defence observed in chronic alcohol abuse could also be explained by the insufficient endogenous P5P formation.

Kryptopyrroluria – metabolic disorder with many symptoms

The metabolic disorder hemopyrrollactamuria (HPU), formerly called kryptopyrroluria (KPU), is a disorder of pyrrole excretion. Pyrroles are normally excreted via the bile pigment in the stool. In hemopyrrollactamuria, the pyrroles are excreted through the kidneys and urine. This leads to complex formation with zinc and vitamin B₆. As a result, this disease can lead to a deficiency of these micronutrients.

Activated Vitamin B₆ - pyridoxal 5-phosphate (P5P)

Vitamin B₆ is a collective term for all vitamin 3-hydroxy-2-methylpyridines. These include pyridoxine, pyridoxal and pyridoxamine, which can be converted into one another during metabolism. Pyridoxal 5-phosphate (P5P) is formed in the liver from pyridoxal as one of the phosphorylated coenzyme forms of vitamin B₆. With sufficient supply, the total amount of vitamin B₆ in the bodyis about 100 mg, 80% of which is stored in the muscles in the form of P5P linked to glycogen phosphorylase. P5P is therefore the most important storage form for vitamin B₆. Its half-life in blood plasma is approximately 30 days (1). In blood plasma, P5P is bound to albumin, which makes it less able to be filtered through the glomeruli and thus is excreted more slowly than other vitamin B₆ forms. In the intermediate metabolism of amino acids, the amino groups are split off by deamination reactions and transferred to alpha-keto acids in order to then serve in the synthesis of carbohydrates or fats. P5P serves as a central coenzyme in these processes. In addition, P5P is a cofactor in the decarboxylation of amino acids that lead to the formation of biogenic amines. These include numerous neurotransmitters such as dopamine or serotonin. The activated form of vitamin B₆ is also involved in the formation of porphyrins such as hemoglobin, in collagen synthesis and in the mobilization of glycogen (2).

Advantages of Vitamin B₆ activated

Vitamin B₆ may cause itching and numbness in when taken in higher therapeutic doses. With high vitamin B₆ doses, the liver is probably unable to convert the pyridoxine ingested into P5P. However, these incompatibilities do not occur when taking P5P itself. P5P can also cross the blood-brain barrier more easily than pyridoxine. Therefore, for neurological indications P5P is more efficient (18) and is preferable to non-activated pyridoxine.

Reference values

Parameters	substrate	reference value	Description
Pyridoxal-5‘-phosphate (P5P)	Serum	3.3 - 9.2 µg/l	Fasting (12 h). Protect from light during storage and transport. P5P is the most abundant vitamin B₆ metabolite, therefore only P5P is usually determined.
	Whole blood	11.3 - 22.5 µg/l
Aspartate aminotransferase activation coefficient (AST)	Red cell hemolysate	> 2.0	Enzymatic UV test to determine the activity of this enzyme without or with the addition of PLP. This is used to determine an activation coefficient.
Interpretation
Low values: P5P		Indication of vitamin B₆ deficiency
High values: AST activation coefficient		Indication of vitamin B₆ deficiency

Nutrigenetics
Characteristic gene sites and their effects on vitamin requirements

Gene	rsNumber	risk SNP	Description	Recommended nutrients
MTHFR	rs1801133	T	The transmethylation by this enzyme is reduced, the need for folic acid and vitamin B6 is increased This SNP is associated with increased homocysteine levels. Vitamin B2 (riboflavin) can increase the activity of the MTHFR enzyme, therefore an increased intake is recommended. Vitamin B6 and folic acid should always be taken together with vitamin B12 (19)(20)(21)(22).	B₂, B₆, B₁₂ and folic acid

Deficiency symptoms

Impact on	Symptomatology
General health	Irritability, nervous and depressive mood, insomnia
Blood	Hyperhomocysteinemia Hypochromic, microcytic anemia
Skin/Mucosa	Dermatitis, Glossitis, Stomatitis, Cheilosis
Nervous system	Pareses, ataxias (due to glutamate metabolism disorders) Peripheral neuropathy, demyelination, sensory disorders, epileptic cramps, tremor
Immune system	Immunodepression
Musculature	Muscular atrophy, muscle weakness

Indications

Effect	Indication	Dosage
Physiological effects at a low intake	For general prevention	10 - 50 mg/d
	Therapeutic support for PMS, especially for premenstrual depression and dismenorrhoe	100 - 300 mg/d
	Therapeutic support for carpal tunnel syndrome	100 - 300 mg/d
	Therapeutic support for diseases associated with alcohol abuse	50 - 100 mg/d
	Therapeutic support for chronic fatigue syndrome	50 - 100 mg/d

Administration

General mode of administration
When	B vitamins can be taken with or between meals.
Side effects
No side effects are known to date.
Contraindications
No contraindications are known to date.

Interactions

Drug interactions
Estrogens (oral contraceptives)	Estrogens increase the need for vitamin B₆. Vitamin B₆ deficiency leads to serotonin deficiency.
Anti-Parkinson’s (e.g. L-Dopa, Carbidopa)	Vitamin B₆ accelerates the peripheral conversion of L-dopa to dopamine.
Neuroleptics (e.g. haloperidol)	High vitamin B₆– doses can reduce the occurrence of extrapyramidal effects.
Methotrexate	High vitamin B₆–doses help to reduce the side effects under methotrexate therapy.
Asthma drug (theophylline)	Theophylline can increase vitamin B₆-demand.
Nutrient interactions
Trace elements	Magnesium, iron and zinc show supportive effects on vitamin B₆-effects.
Vitamins	Vitamin B₆ acts synergistically with all B vitamins, especially with folic acid and B₁₂. Vitamin B₂–deficiency increases the excretion of vitamin B_6. Nicotinic acid acts as an antagonist in pharmacological doses.
Vitaminoids	Coenzyme Q10 and vitamin B₆ show synergistic effects

Description and related substances

Description

Water-soluble vitamin of the B complex

Related substances

Permitted:

Pyridoxine hydrochloride
Pyridoxine-5′ phosphate
Pyridoxal-5′ phosphate

References

(1) Biesalski HK, Köhrle J, Schümann K: Vitamine, Spurenelemente und Mineralstoffe. 2002.
(2) Hahn A, Ströhle A, Wolters M: Ernährung. Physiologische Grundlagen, Prävention, Therapie. 2005.
(3) Niestroj Irmgard: Praxis der orthomolekularen Medizin. 2000.
(5) Aufiero E, Stitik TP, Foye PM, Chen B: Pyridoxine hydrochloride treatment of carpal tunnel syndrome: a review. Nutr Rev 2004; 62 (3): 96-104.
(6) Wyatt KM, Dimmock PW, Jones PW, Shaughn O’Brian PM: Efficacy of Vitamin B6 Treatment of premenstrual syndrome: systematic review. BMJ 1999; 318 (7195): 1375-81.
(7) Williams AL, Cotter A, Sabina A: Girard C, Goodman J, Katz DL: The role for Vitamin B6 as treatment for depression: a systematic review. Fam Pract 2005; 22 (5): 532-7.
(8) Gröber U: Arzneimittel und Mikronährstoffe. Medikationsorientierte Supplementierung. Wissenschaftliche Verlagsgesellschaft Stuttgart. 2012.
(9) Morris MS et al: Plasma pyridoxal 5'-phosphate in the US population: the National Health and Nutrition Examination Survey, 2003-2004. Am J Clin Nutr. 2008 May; 87 (5): 1446-54.
(10) Resch J., Viebahn I: Mikronährstoffe auf dem Prüfstand. Biogena Studie 2011.
(11) Zhang SM: Plasma folate, vitamin B6, vitamin B12, homocysteine and risk of breast cancer. J Natl Cancer Inst. 2003 Mar 5; 95 (5): 373-80.
(12) Gröber U: Mikronährstoff. Metabolic Tuning – Prävention – Therapie, Wissenschaftliche Verlagsgesellschaft Stuttgart 2011.
(13) Lussana F et al: Blood levels of homocysteine, folate, vitamin B6 and B12 in women using oral contraceptives compared to non-users. Thromb Res. 2003; 112 (1-2): 37-41.
(14) Koronare Herzerkrankungen: In Österreichischer Ernährungsbericht 2003. Hrsg: Bundesministerium für Gesundheit und Frauen.
(15) Stanger O, Herrmann W, Pietrzik K, Fowler B et al: DACH-LIGA homocystein consensus paper on the rational clinical use of homocysteine, folic acid and B-vitamins in cardiovascular and thrombotic diseases: guidelines and recommendations. Clin Chem Lab Med 2003; 41 (11): 1392-403.
(16) Chiang EP, Selhub J, Bagley PJ, Dallal G, Roubenoff R: Pyridoxine supplementation corrects vitamin B6 deficiency but does not improve inflammation in patients with rheumatoid arthritis. Arthritis Res Ther 2005; 7 (6): R1404-11.
(17) Chen CH, Chang SJ, Lee BJ, Lin KL, Huang YC: Vitamin B(6) supplementation increases immune response in critically ill patients. Eur J Clin Nutr 2006. Oct; 60 (10): 1207-13.
(18) Fuchs N: Mit Nährstoffen heilen, 2001.
19 Olteanu, H. Munson, T. Banerjee, R. 2002. Differences in the efficiency of reductive activation of methionine synthase and exogenous electron acceptors between the common polymorphic variants of human methionine synthase reductase. Biochemistry. 41(45):13378-85. .
20 Wilson, A. et al. 1999. A common variant in methionine synthase reductase combined with low cobalamin (vitamin B12) increases risk for spina bifida. Mol Genet Metab. (4):317-23.
21 Seibold, P. et al. Polymorphisms in oxidative stress-related genes and postmenopausal breast cancer risk. Int J Cancer. 129(6):1467-76.
22 Jiang-Hua, Q. et al. 2014. Association of methylenetetrahydrofolate reductase and methionine synthase polymorphisms with breast cancer risk and interaction with folate, vitamin B6, and vitamin B 12 intakes. Tumour Biol. 35(12):11895-901.

References Interactions:
(1) Stargrove Mitchell Bebel, Treasure Jonathan, McKee Dwight L.: Herb, Nutrient, and Drug Interactions: Clinical Implications and Therapeutic Strategies. 2008
(2) Gröber Uwe: Mikronährstoffe. Metabolic Tuning – Prävention – Therapie. 3. Auflage, 2011
(3) Gröber Uwe: Arzneimittel und Mikronährstoffe. Medikationsorientierte Supplementierung. 2. Auflage, 2012