Supplementation with high concentrations of synthetic B6 (pyridoxine) leads to decreased natural vitamin B6 (pyridoxal) function

[Gondwanaland]

https://www.ncbi.nlm.nih.gov/m/pubmed/28716455/

The vitamin B6 paradox: Supplementation with high concentrations of pyridoxine leads to decreased vitamin B6 function.
Vrolijk MF, et al. Toxicol In Vitro. 2017.

Abstract
Vitamin B6 is a water-soluble vitamin that functions as a coenzyme in many reactions involved in amino acid, carbohydrates and lipid metabolism. Since 2014, >50 cases of sensory neuronal pain due to vitamin B6 supplementation were reported. Up to now, the mechanism of this toxicity is enigmatic and the contribution of the various B6 vitamers to this toxicity is largely unknown. In the present study, the neurotoxicity of the different forms of vitamin B6 is tested on SHSY5Y and CaCo-2 cells. Cells were exposed to pyridoxine, pyridoxamine, pyridoxal, pyridoxal-5-phosphate or pyridoxamine-5-phosphate for 24h, after which cell viability was measured using the MTT assay. The expression of Bax and caspase-8 was tested after the 24h exposure. The effect of the vitamers on two pyridoxal-5-phosphate dependent enzymes was also tested. Pyridoxine induced cell death in a concentration-dependent way in SHSY5Y cells. The other vitamers did not affect cell viability. Pyridoxine significantly increased the expression of Bax and caspase-8. Moreover, both pyridoxal-5-phosphate dependent enzymes were inhibited by pyridoxine. In conclusion, the present study indicates that the neuropathy observed after taking a relatively high dose of vitamin B6 supplements is due to pyridoxine. The inactive form pyridoxine competitively inhibits the active pyridoxal-5'-phosphate. Consequently, symptoms of vitamin B6 supplementation are similar to those of vitamin B6 deficiency.

 

[Asklipia]

The neuropathy observed after taking a relatively high dose of vitamin B6 supplements is due to pyridoxine. The inactive form pyridoxine competitively inhibits the active pyridoxal-5'-phosphate.

Very good find!

 

[alicec]

Yes very interesting find.

 

[aquariusgirl]

Damn I do better in B6 than in P5p .....what's the threshold for inhibiting those other enzymes?

 

[liverock]

https://www.ncbi.nlm.nih.gov/m/pubmed/28716455/

From the introduction to the study it appears that they are trying to imply that the neurological pain that was suffered was due to high pyroxidine buildup due to pyroxidine in effect lowering P5P the active form of B6.

This test was an in vitro study, In practice(not a lab test) high serum pyridoxine and low P5P levels are quite often due to the MTHFR gene mutations. Increasing folate and B12 will increase methylation and conversion of pyridoxine to P5P to solve the problem.

http://www.side-effects-site.com/vitamin-b6-side-effects.html

 

[bertiedog]

Would anybody have a view as to whether 50 mg daily of this vitamin could play a part in causing severe migraines? I have been trying to work out what could be causing my problems and hadn't realised I was taking such a high dose?

Pam

 

[Gondwanaland]

Would anybody have a view as to whether 50 mg daily of this vitamin could play a part in causing severe migraines?

Yes, I had that with P5P. I assume it is serotonin build up (= B2 deficiency)

This test was an in vitro study, In practice(not a lab test) high serum pyridoxine and low P5P levels are quite often due to the MTHFR gene mutations. Increasing folate and B12 will increase methylation and conversion of pyridoxine to P5P to solve the problem.

Thanks for that. This explains why the in vitro study perfectly matches my experience. When I first started taking B vits I would always get symptoms of B6 deficiency no matter how high or low my B6 intake was. It was only when I took P5P that I felt how a healthy B6 metabolism feels. B12 and folate cause me B1 deficiency.

Damn I do better in B6 than in P5p .....what's the threshold for inhibiting those other enzymes?

I suppose your body will tell you.

 

[alicec]

In practice(not a lab test) high serum pyridoxine and low P5P levels are quite often due to the MTHFR gene mutations. Increasing folate and B12 will increase methylation and conversion of pyridoxine to P5P to solve the problem.

I read the article you linked. It is nonsense. The MTHFR gene does NOT

regulate the conversion of Vitamin B6, Vitamin B12 and folic acid into their ‘active’ forms in the blood

The gene codes for an enzyme which converts 5,10 methylene THF to methyl THF - so yes it does create ONE of the active forms of folate, but it does not act on folic acid.

MethylTHF does in turn replenish the methyl group on methylB12 used in the methionine synthase reaction, so indirectly, yes, MTHFR is important for B12 function.

Activation of B6, however, involves phosphorylation (addition of a phosphate group), not methylation. It has nothing to do with MTHFR.

 

[Gondwanaland]

MethylTHF does in turn replenish the methyl group on methylB12 used in the methionine synthase reaction, so indirectly, yes, MTHFR is important for B12 function.

Activation of B6, however, involves phosphorylation (addition of a phosphate group), not methylation. It has nothing to do with MTHFR.

I do not question that, but I suppose that the methylation cycle gears in the urea cycle, so could it be an indirect activation?

Choline is a methyl donor ("system input") and it increases the need for B2 ("system output").

 

[liverock]

I read the article you linked. It is nonsense. The MTHFR gene does NOT

The gene codes for an enzyme which converts 5,10 methylene THF to methyl THF - so yes it does create ONE of the active forms of folate, but it does not act on folic acid.

MethylTHF does in turn replenish the methyl group on methylB12 used in the methionine synthase reaction, so indirectly, yes, MTHFR is important for B12 function.

Activation of B6, however, involves phosphorylation (addition of a phosphate group), not methylation. It has nothing to do with MTHFR.

Thanks for the extra information. I just take folate and B12 when I get a build up of pyroxidine which for me seems to go hand in hand with low B12 symptoms.

 

[alicec]

I do not question that, but I suppose that the methylation cycle gears in the urea cycle, so could it be an indirect activation?

Sorry - I don't follow the links. What is the connection between methylation and the urea cycle and what in turn does the urea cycle have to do with B6 activation?

Choline is a methyl donor ("system input") and it increases the need for B2 ("system output").

Sorry again I don't follow the connection. Do you mean that anything which stimulates methylation will increase need for B2 and that this in turn might affect B6 activation (adversely) since B2 is required in this process?

Even if this were the case, and I'm not sure that it is, the article is saying the opposite - it claims increasing methylation will increase activation of B6.

 

[Gondwanaland]

http://intelegen.com/nutrients/prevent_the_damaging_effects_of_.htm

Acetaldehyde induces a deficiency of Pyridoxal-5-Phosphate (P5P). P5P is the major coenzyme necessary to form virtually all major brain neurotransmitters.10

It is involved in all transamination reactions, whereby cells may convert many different amino acids into each other to satisfy their ever-shifting amino acid needs.10

P5P is necessary to convert essential fatty acids into their final use forms, as well as to turn linoleic acid into the key, nerve cell-regulating biochemical, Prostaglandin E1.15

P5P helps regulate magnesium entry into cells,16 and the level of excitability of nerve cells is strongly dependent upon their magnesium level.

P5P is also necessary to convert vitamin B3, niacin/niacinamide, into the active coenzyme form, NAD.17

Unfortunately for P5P (and we humans who are so dependent on it), AH is known to strongly combine with the protein portion of P5P enzymes in a way that displaces the P5P portion of the molecule. This subjects P5P to an increased rate of destruction and results in abnormally low blood and tissue levels of this coenzyme.1,18

 

[Asklipia]

Acetaldehyde is detoxified by B1, is it not? Subsequently inducing Thiamine Deficiency.
Maybe this is how taking a lot of thiamine has boosted my B6 levels (seen by increased dreaming).
Nice to start the day with a puzzle solved!

 

[Gondwanaland]

Acetaldehyde is detoxified by B1, is it not? Subsequently inducing Thiamine Deficiency.

+ Molybdenum

http://lpi.oregonstate.edu/mic/minerals/molybdenum
The molybdenum atom is part of the molybdenum cofactor in the active site of four enzymes in humans: sulfite oxidase, xanthine oxidase, aldehyde oxidase, and mitochondrial amidoxime reducing component.
http://lpi.oregonstate.edu/mic/minerals/molybdenum#acquired-deficiency
....
Patients with ISOD and MocoD were also found with elevated excretion of α-amino adipic semialdehyde (α-AASA) (29). α-AASA accumulation is the metabolic signature of a deficiency in α-AASA dehydrogenase observed in patients with pyridoxine-dependent epilepsy. The enzymatic deficiency in these individuals causes an increase in α-AASA and its cyclic form piperideine-6-carboxylate (P6C). P6C can trap pyridoxal-5-phosphate (PLP), the active form of vitamin B6 (pyridoxine), leading to a deficiency in PLP, which is corrected with supplemental pyridoxine. A decrease in PLP has also been observed in the cerebrospinal fluid from ISOD and MocoD patients (30). It is not clear whether sulfite is responsible for the accumulation of α-AASA and the deficiency in PLP in ISOD and MocoD patients. Nevertheless, pyridoxine and folic acid supplementation in patients with MocoD successfully normalized the PLP level and abolished seizures in two patients with mutations in MOCS2(MocoD Type B) (31). Although anti-seizure medications and dietary restriction of sulfur-containing amino acids may be beneficial in some cases (32), there are no treatment options for patients with mutations in the MOCS2, GPHN (MocoD Type C), or SUOX genes. Pyridoxine supplementation is a new option being considered to alleviate specific clinical features in patients.

I have run into problems with P5P only, and now I understand this recommendation:

http://www.acu-cell.com/bx2.html
When supplementing more than 50mg of Vitamin B6 / Pyridoxine per day, the tablets should contain a small percentage of the Vitamin as Pyridoxal-5-Phosphate (P5P).

ETA

http://whfoods.org/genpage.php?tname=nutrient&dbid=128
this mineral [Molybdenum] has been shown to be required for the activity of at least seven enzymes in our body, and numerous body systems rely on these enzymes for support.

 

[Bluelude1]

Does this mean that people with high B6 levels / MTHFR should opt for P5P exclusively or use it in conjunction with Pyridoxine HCL?

Currently, I take 1000mg Pyridoxine HCL & 100mg P5P, but I've been trying to get to the bottom of whats causing such a high dose requirement to mitigate deficiency symptoms. I find if it's not handling symptoms some days I've tried additional Pyridoxine HCL, but I promptly end up with neuropathy and restless legs every time. My dad is at the exact same dose and swears taking an additional 50mg of P5P (150mg total a day) does a better job.

We try not to go over 100mg P5P a day because that's supposedly the safe limit, but this thread has me wondering if there is more to the story.

 

[alicec]

Does this mean that people with high B6 levels / MTHFR should opt for P5P exclusively or use it in conjunction with Pyridoxine HCL?

It suggests that pyridoxal forms of the vitamin (as far as I know only pyridoxal 5 phosphate is available) are the best option for everyone, but particularly for people who have high needs.

MTHFR has nothing to do with B6.

We try not to go over 100mg P5P a day because that's supposedly the safe limit,

Based on what?

The study suggests your father's observation are worth following up. Have you ever tried ditching the pyridoxine altogether? Maybe it is the cause of your problems since it can compete with the active vitamin.

 

[Bluelude1]

Based on what?

That's just the amount I've heard repeatedly not to exceed of P5P. Not sure what the "real" limit is.

Have you ever tried ditching the pyridoxine altogether?

I haven't until I ran across this thread, but I am planning to make the change immediately and see what happens.

 

[JES]

The number one safety issue from excessive B6 is nerve damage, but this only applies to regular B6, AFAIK P5P does not have this side effect, so if anything it should be safer to exceed the dosage with it. The one thing to keep in mind is that P5P is more concentrated than regular B6. I notice a serotonin kick from much smaller dosages of P5P than B6, which makes me sleepy etc. So probably you want to take at least five times less P5P than normal B6.

 

[Bluelude1]

AFAIK P5P does not have this side effect, so if anything it should be safer to exceed the dosage with it.

Wouldn't you have to still be mindful considering its the active form and wouldn't have the same rate limiting protections that Pyridoxine HCL would have?

The one thing to keep in mind is that P5P is more concentrated than regular B6... So probably you want to take at least five times less P5P than normal B6.

Apparently P5P is 5x more potent then B6

 

[JES]

Wouldn't you have to still be mindful considering its the active form and wouldn't have the same rate limiting protections that Pyridoxine HCL would have?

The user reports and conventional wisdom over the Internet suggests that P5P would not have this side effect. However, remember that this is only anecdotal evidence, I doubt any medical studies has been done comparing B6 to P5P. I found one case online where a person reported the same neuropathy side efffect from P5P (source). I guess the likelihood of this is down to genetics as well. I could never get near those dosages anyway.