Vitamin B6

1.1. Origin and Composition

The term 'Vitamin B6' refers to a collection of molecules (vitamers) all sharing a structure similar to the pyridoxine molecule, possessing the form of pyridoxal 5'-phosphate (PLP) after ingestion which acts in the human body as an essential vitamin.

The role of PLP in the human body is mostly that of a coenzyme (similar to many essential minerals like zinc), being required in sufficient amounts to allow proper functioning of certain enzymes.^[2] The enzymes that PLP helps function are mostly involved in cellular proliferation and regulation^[3] while low serum vitamin B6 status seems to be correlated with a few cancerous states (abnormalities in cellular proliferation and regulation).^[4][5][6][7]

1.2. Sources and Structure

Dietary forms of vitamin B6 include:

• Pyridoxine

• Pyridoxal

• Pyridoxamine

1.3. Biological Significance

After intestinal absorption, these dietary/supplemental forms of B6 which are considered inactive are converted into the bioactive pyridoxal 5'-phosphate (PLP) in the liver^[8] and intestines themselves^[9] and then bound to serum albumin^[10] to be transported to peripheral tissue.

All three major dietary forms of vitamin B6 (pyridoxine, pyridoxal, and pyridoxamine) are initially subject to the enzyme pyridoxal kinase^[11] which adds a phosphate group at the 5' position, although only in the case of pyridoxal does this process form PLP; the product of pyridoxine (pyridoxine 5'-phosphate) and that of pyrixodamine (pyridoxamine 5'-phosphate) both need to be additionally subject to the enzyme pyridox(am)ine phosphate oxidase to finally produce PLP.^[12]

PLP can be hydrolyzed back into pyridoxal via PLP phosphatase, and this enzyme can also work on pyridoxine-5'-phosphate to convert it back into pyridoxine.^[13] This must occur for pyridoxal to be subject to aldehyde oxidase to produce the urinary metabolite 4-pyridoxic acid (4-PA) which is the end product of vitamin B6 metabolism.

2.1. Absorption

It was initially thought that intestinal uptake of vitamin B6 as pyridoxine hydrochloride,^[14][15] pyridoxal (including its phosphate form^[16]), and pyridoxamine (as well as its phosphate^[17]) were via passive diffusion in the rat.

Human studies on isolated intestinal cells (Caco-2) have noted a saturatable transporter which is concentration and pH dependent, capable of absorbing PLP and pyridoxamine;^[18] this is in contrast to a colonic transporter which which does not uptake PLP^[19] and neither transporter appears to be capable of uptaking pyridoxamine.^[18][19]

Mechanistically, there appear to be transporters for vitamin B6 vitamers which absorb pyridoxamine; in the jejunem (main site of absorption in the intestines) pyridoxal-5'-phosphate may also be absorbed

When tested in situ with jejunal segments, it was noted that while a few fiber types (cellulose, pectin, and lignan) did not influence absorption rates while homogenized carrots at 1-3% of the medium reduced the absorption of pyridoxamine and pyridoxal but not pyridoxine.^[20] This may be related to how a synthetic solution of pyridoxine is more bioavailable than a similar dose via orange juice,^[21] even though adding sugar to the synthetic solution enhances bioavailability (via intrajejunal infusion).^[21]

3.1. Dopaminergic Neurotransmission

The enzyme that converts L-DOPA into active dopamine, L-dopa decarboxylase, is a pyridoxine-5'-phosphate (PLP) dependent enzyme^[22] and due to the actions of pyridoxine infusion paralelling that of dopamine (in regards to prolactin and growth hormone) it is thought that additional pyridoxine increases the activity of this enzyme particularly in the hypothalamus.^[23] It is known that a deficiency of PLP hinders the activity of this enzyme in the brain.^[24] 

3.2. Serotonergic Neurotransmission

Rats deficient in pyridoxine have significantly reduced hypothalamic levels of both pyridoxal phosphate (PLP) and serotonin, which seem to result in low plasma prolactin levels; since the plasma prolactin was remedied with a 5-HT_1A agonist, it was thought that a deficiency in pyridoxine reduces activity of this serotonin receptor in the hypothalamus.^[25]

3.3. Hallucination and Euphoria

Pyridoxine has been suggested to be a contributor to inducing dreams due to its interaction with l-dopa decarboxylase crossing over into dopamine and serotonin production. Serotonin based drugs (such as SSRIs) have been noted to increase subjective dream intensity^[26] and it is hypothesized that increased arousal during REM sleep (when dreaming appears to occur most frequently) and subsequent waking may underlie the increases in dream intensity and frequency reported with pyridoxine.

When testing dream salience (subjective intensity of a dream) as self-reported after a night of sleep, 100mg and 250mg pyridoxine showed dose-dependent increases in dream salience relative to placebo.^[27]

4.1. Mechanisms

Increasing the pyridoxal-5'-phosphate (PLP) content of 3T3-L1 adipocytes to the range of 50-100nM appears to dose-dependently reduce intracellular calcium in the range of 12-36% with a similar reduction in fatty acid synthase (FAS) activity and expression.^[1] This is thought to be a result of pyridoxine's negative regulation of calcium signalling in general^[28] and the adipogenic actions of calcium in body fat tissue.^[29][30]

4.2. Weight

Supplementation of a combination of leucine (2.25g) with pyridoxine (30mg) in overweight persons has been noted to reduce the respiratory exchange ratio by 0.019 units (calculated to increase fat loss by 33.6g daily) relative to placebo.^[1]

5.1. Corticosteroids

Transcriptional activity of glucocorticoid receptors seems to be inversely related to cellular concentrations of pyridoxal 5'-phosphate (PLP) with higher concentrations suppressing activity.^[31][32] Mimicking a mild deficiency (adding no pyridoxine to medium) can increase activity of the receptor 98% whereas elevating PLP (1,000µM) can suppress activity 48%.^[33]

One study using 200mg pyridoxine twice daily in 10 otherwise healthy women failed to note any changes in cortisol or ACTH relative to baseline.^[34]

5.2. Growth Hormones

While 1,000μM of bioactive pyridoxine is able to inhibit growth hormone secretion from pituitary cells, lower concentrations of 1-100μM in primary rat pituitary cells have failed to have an effect.^[35]

Supplementation of pyridoxine in otherwise healthy women acutely (200mg twice daily) failed to significantly increase growth hormone secretion over 24 hours, causing a nonsignificant trend to increase nighttime growth hormone.^[34]

During physical exercise with an infusion of 600mg pyridoxine administration of the drug was associated with a larger increase in growth hormone levels in serum during a cycling test, although control appeared to have slightly lower serum pyridoxine at baseline^[36] and a lower dosed infusion of 300mg has been noted elsewhere to increase growth hormone in hospitalized persons acutely.^[23]

5.3. Prolactin

In rats, a deficiency of vitamin B6 results in an increase in plasma prolactin concentration.^[25]

Pyridoxal phosphate (PLP) is able to inhibit pituitary cell proliferation in vitro in various cell lines (MMQ, AtT-20, GH3) between 10-1,000μM not associated with toxicity and in a reversible manner after PLP removal,^[35] this reduction in proliferation being associated with less hormone secretion and in primary rat pituitary cells 1μM is able to suppress prolactin secretion to 66% of control (48% at 10μM) without affecting growth hormone.^[35]

Vitamin B6 appears to have a generally suppressive effect on prolactin, with a deficiency in B6 causing higher than normal serum B6 concentrations and increasing concentrations causing further suppressions of prolactin

A suppression of prolactin increases have been noted in various rodent studies with infusions of pyridoxine, including a hindering of a chlorpromazine^[37] and opioid^[38] induced prolactin spike.

There may be a slight suppression of prolactin concentrations acutely in women given 200mg pyridoxine twice daily when measuring blood over the course of 24 hours, relative to baseline values.^[34]

The increase in prolactin seen during exercise has been noted to be fully abrogated with continuous infusion of 600mg pyridoxine.^[36]

6.1. Breast Cancer

When assessing plasma pyridoxal-5'-phosphate (PLP) concentration in menopausal women, serum PLP appeared to be inversely associated with breast cancer risk when assessing prediagnostic values as the highest quartile (greater than 116.6nM) had 30% less risk than the lowest quartile (less than 41.1nM).^[39]

6.2. Adjuvant Usage

Hand-foot syndrome (HFS), a reddening of the hands and soles of the feet commonly seen with usage of the chemotherapeutic capecitabine,^[40] has traditionally been claimed to reduce these symptoms with mixed results. This traditional usage arose due to the visual similarities between HFS and rat acrodynia caused by pyridoxine deficiency^[41] and due to a pilot study where four out of five persons given 50-150mg pyridoxine after HFS developed (from intravenous 5-fluorouracil) found benefits to symptoms.^[42]

50mg pyridoxine thrice daily over 12 weeks (150mg each day) in persons with breast or colon cancer on capecitabine therapy failed to significantly reduce symptoms incidence, severity, or dose modification of capecitabine due to symptoms relative to placebo;^[43] there were some positive trends that failed to reach significance most notable for symptom severity, and pyridoxine had no influence on cancer outcomes.^[43]

7.1. COX Inhibitors

COX inhibitors are a class of antiinflammatory drugs of which include NSAIDs like aspirin.

It appears that in a cohort of persons using NSAIDs relative to those not on the drugs, those using NSAIDs have a lower concentration of bioactive B6 (pyridoxal-5'-phosphate) which was time dependent with larger decreases seen with longer drug usage;^[44] decreases in liver and kidney PLP concentration was noted in rats and mice on NSAIDs for prolonged periods of time.^[44]

7.2. ZMA

ZMA is a formulation named after the acronym of Zinc and Magnesium (as Aspartate chelate) but routinely includes the addition of vitamin B6.

The inherent 5α-reductase inhibitory effect of zinc (which would increase testosterone via reducing its conversion into the androgen DHT) occurs at too high a concentration to be relevant to supplementation at 15mM in vitro, and the addition of high concentrations of pyridoxine appear to reduce the required amount of zinc for this effect down to 1.5-3mM.^[45] This information is still not thought to apply to dietary supplementation, since zinc is associated with an increase in DHT after supplementation^[46] which occurs at the level of the 5α-reductase enzyme at 500nM (0.5µM).^[47]

8.1. Pyridoxine Neuropathy

Pyridoxine neuropathy refers to a particular form of neuropathy (nerve damage) where high doses of any vitamin B6 vitamer can, over time, cause adverse symptoms^[48] mostly characterized in humans when doses exceeding 6,000mg are taken for longer than one year with the primary symptoms of sensory ataxia, diminished distal limb proprioception, paresthesia, and hyperesthesia.^[48][49][50] 

At least one study noted a case where some adverse effects were noted at as little as 200mg (11,700% the RDI and 200% the TUL)^[51] although most dog studies where neuropathy is successfully replicated have used 50-300mg/kg^[52][53][54] (estimated human range of 27-162mg/kg and, for a 150lb person, at least 1.8g; similar estimated ranges from rat data^[55][56]). Toxicity can be exerted in as little as 1-15 days in rats, although it requires 600-1,200mg/kg via intraperitoneal infusion.^[56][57][58]

There also appear to be two toxic 'levels', with the lower dose being an axonopathy (destruction of axons) which appears to be reversible upon pyridoxine discontinuation and the higher level being an irreversible sensory ganglion neuropathy.^[56][59]

Vitamin B6 is known to be highly toxic when megadosed for a prolonged period of time, at best causing peripheral neuropathy that can be repairable and at worst causing irreversible sensory ganglion neuropathy. The lowest estimate this toxic dose has been reported is at 200mg (11,700% the RDI) while it is reliable induced at around 5g (300,000% the RDI) or higher intake in humans