Pyridoxine Is Toxic And Inhibit P5P Function?

[GutFeeling]

The vitamin B6 paradox: Supplementation with high concentrations of pyridoxine leads to decreased vitamin B6 function. - PubMed - NCBI

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

 

[haidut]

The vitamin B6 paradox: Supplementation with high concentrations of pyridoxine leads to decreased vitamin B6 function. - PubMed - NCBI

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

Yep. And the older the person the less pyridoxine they are able to convert into P5P. That's one of the main reasons we use P5P in our Energin and not the pyrodoxine Hcl. The latter will probably work OK in people under 30 but its (neuro)toxicity becomes rather obvious with advancing age and in doses higher than 25mg daily.

 

[Steven Bussinger]

Crepes, I'll have to get P5P next time, then. I take Energin in the day, but use 100mg pyridoxine HCL before bed.

 

[sunraiser]

Crepes, I'll have to get P5P next time, then. I take Energin in the day, but use 100mg pyridoxine HCL before bed.

I think it's an extreme amount to be taking each day, but to each his own. The following quote is from this paper:

http://www.efsa.europa.eu/sites/default/files/scientific_output/files/main_documents/760.pdf

Only dephosphorylated B6 vitamers can be transported into the cells (Coburn et al., 2003) indicating that the bioavailability of intact pyridoxal 5’-phosphate upon oral intake would be low. Removal of the phosphate group is a function of alkaline phosphatases, which are encoded by at least four different genes producing tissue non specific, intestinal, placental and germ cell alkaline phosphatases (van Hoof and De Broe, 1994). The tissue non-specific alkaline phosphatase is the one predominantly involved in vitamin B6 metabolism and it is located anchored to the ectoplasmic side of the plasma membrane. Given that the bioavailability of pyridoxal 5’-phosphate requires hydrolysis of the phosphate group before absorption through the intestinal layer may occur, one can conclude that the bioavailability of vitamin B6 from pyridoxal 5’-phosphate will be lower than or at best similar to the bioavailability of pyridoxine.

Basically it would suggest that p5p has to be dephosphorylated before intestinal absorption regardless, so it's likely to have far lower bioavailability. This would very likely account for the perceived "lack" of toxicity as it simply wouldn't be being absorbed to large degrees in many people.

HOWEVER, I have read that people with leaky gut may technically miss this step as some might be absorbed before it reaches the intestines and it can provide them benefit for a temporary time (as p5p). Also just to note I have read experiences of people getting severe peripheral neuropathy from p5p as well as B6 (Hcl), so it's not to say it's completely inert.

It's also possible there's some metabolic need for the phosphorylation step of B6 and that it's not simply making it bioavailable, but it's doing something else that has a physiological purpose.

It isn't as black and white as this post makes out, that's all I know.

Again, I can't fathom 100mg per day being a sustainable intake, but you obviously have your own internal compass and experiences to guide you.

 

[Steven Bussinger]

That's what a single capsule is, 100mg. I guess it is a lot, since it's 500x the RDI. I'll order a better supplement.

 

[sunraiser]

That's what a single capsule is, 100mg. I guess it is a lot, since it's 500x the RDI. I'll order a better supplement.

You could just cut up your tablet. Maybe take half a pill every 7 days, or half the capsule contents.

It'd put things in a much more reasonable range. You'll be able to judge your experience and need better than my guess work ever can, though!

 

[Antonello]

@haidut I'm wondering if this study on plain version of B6 can replicate what happen with B2 as I'm noticing two completely different effects from the plain riboflavin and the R5P.

 

[haidut]

@haidut I'm wondering if this study on plain version of B6 can replicate what happen with B2 as I'm noticing two completely different effects from the plain riboflavin and the R5P.

Yes, the same is known to happen for riboflavin Hcl. Both B2 and B6 in their Hcl form can be toxic in higher amounts due to lack of conversion into the phosphorylated forms. The issue becomes more and more pertinent with advancing age or illness, as phosphorylation of both pro-vitamins depends on ATP, which is obviously low when somebody is older/sicker.
Pyridoxal kinase - Wikipedia

 

[GreekDemiGod]

Started taking pyridoxine 8 mg / day. You guys think it's too high of a dose?

 

[Max23]

Started taking pyridoxine 8 mg / day. You guys think it's too high of a dose?

That is a very low dose. I doubt it´ll have any effects. I didn´t have much effects from 50. When I increaseed it to 150 I got great results, which seem to be fading after ten days or so. Looking for to get P5P and riboflavin.

 

[charlie]

I think it was Dr. Lonsdale who said the B6 toxicities are actually B1 deficiency because B6 depletes B1.

 

[BigChad]

Yes, the same is known to happen for riboflavin Hcl. Both B2 and B6 in their Hcl form can be toxic in higher amounts due to lack of conversion into the phosphorylated forms. The issue becomes more and more pertinent with advancing age or illness, as phosphorylation of both pro-vitamins depends on ATP, which is obviously low when somebody is older/sicker.
Pyridoxal kinase - Wikipedia

When i see riboflavin on multis it just says riboflavin unlike b6 and b1 which mention hcl. What form is plain riboflavin in? Its never stated from what I've seen

 

[ddjd]

When i see riboflavin on multis it just says riboflavin unlike b6 and b1 which mention hcl. What form is plain riboflavin in? Its never stated from what I've seen

you want the active form b2 r5p

 

[Peater]

Yes, the same is known to happen for riboflavin Hcl. Both B2 and B6 in their Hcl form can be toxic in higher amounts due to lack of conversion into the phosphorylated forms. The issue becomes more and more pertinent with advancing age or illness, as phosphorylation of both pro-vitamins depends on ATP, which is obviously low when somebody is older/sicker.
Pyridoxal kinase - Wikipedia

Is this also true of thiamine HCL?

 

[Amazoniac]

- Inter-individual differences in pharmacokinetics of vitamin B6: A possible explanation of different sensitivity to its neuropathic effects

Spoiler

"Although the number of reported cases of neuropathy after using vitamin B6 supplements is still increasing and our previously in vitro results indicate that the inactive PN might be responsible for causing adverse health effects due to inhibition of PLP-dependent enzymes [7], the exact mechanism by which vitamin B6 causes these neuropathic effects is not fully clear."

"Whereas the dose of vitamin B6 in the supplements was previously considered responsible for causing neuropathy [8–10], our previous data indicated that the vitamer present in the supplement is the more important determinant [7]. Of all B6 vitamers, only PN was shown to have cytotoxic effects on cultured neuronal cells. These findings correlate well with in vivo animal studies, where PN induced neuronal damage after intraperitoneal injection, whereas the other vitamers did not induce any damage [11]. Also clinically, the vitamer PN predominantly seems to be causing adverse health effects, as the majority of reported cases to Lareb concerned supplements that contain the inactive vitamer PN. It must be noted that most of the vitamin B6 preparations on the market also contain PN, which could contribute to an overrepresentation of PN induced cases of neuropathy. However, this still highlights that, besides the dose of vitamin B6, the specific vitamer present in the supplements plays an important role in the development of vitamin B6-related neuropathy. Some of the patients reporting neuropathic complaints only used a daily dose of 2 mg vitamin B6, whereas other cases of neuropathy developed after the use of 250 mg. In addition, large differences in plasma levels of PLP between the different cases of B6-induced neuropathies were reported by Lareb [5]. This implies that there seems to be an inter-individual difference in kinetics of vitamin B6 and sensitivity towards its toxicity. Taking into account our in vitro findings, we hypothesized that the accumulation of free PN would be responsible for the toxic effects."

"The present paper aimed to investigate potential inter-individual differences in the pharmacokinetics of vitamin B6. This was done by supplementing 12 healthy volunteers with either 50 mg PLP or 50 mg PN for one week, during which at different days plasma levels of the different vitamers (PL, PLP, PN) of B6 were measured."

"Vitamin B6 was taken during or immediately after a light breakfast that consisted of brown bread with cheese and/or ham or of cruesli with Greek yoghurt." "Subjects were instructed to take one capsule vitamin B6 during or immediately after breakfast for the following six days." "The estimated maximal intake of PN from breakfast was calculated to be 0.3 mg."

"Our results reveal that there is a clear inter-individual difference in metabolism of PN, which might be an explanation for the differences in sensitivity to vitamin B6-related adverse health effects between humans."

"Over the past years, numerous papers have been published reporting neuropathy after administration or supplementation of vitamin B6 [4,5,8,18]. These adverse health events were attributed to the high doses of vitamin B6 being used. However, recent data revealed that toxic effects of vitamin B6 already occurred at doses as low as the recommended dietary allowance."

"Since most of the vitamin B6 supplements on the market contain the biological inactive PN, it needs to be metabolized into the active PLP inside our body. Absorption of vitamin B6 occurs after hydrolysis of the phosphorylated forms by membrane-bound tissue non-specific alkaline phosphatase (TSNALP) in the intestines via passive diffusion [19]. The majority of the absorbed vitamin B6 is metabolized in the liver into PLP by the enzymes pyridoxal kinase, which phosphorylates PL, PM and PN to their phosphorylated forms, and pyridoxine phosphate oxidase, which oxidizes PNP and PMP to PLP [19]. When entering the circulation, PLP will be hydrolyzed into pyridoxal by alkaline phosphatases in order to be taken up by target cells. Once taken up by the target cells, PL will again be phosphorylated to PLP by pyridoxal kinase in order to be active. At high doses, PN is found to saturate pyridoxal kinase and pyridoxine phosphate oxidase, potentially leading to accumulation of PN after chronic supplementation."

"In the present study, plasma levels of the different vitamers were furthermore measured during a one-week supplementation period. Although there was an increasing trend in plasma levels of PN over supplementation of PN for 7 days, accumulation of PN could not be shown. The increased PN levels were not statistically significant due to large standard deviations, indicating large inter-individual differences. Our data were therefore also analyzed at individual level and indeed, large individual differences in plasma PN and PL levels were seen after supplementation with PN. Three out of the six volunteers showed an increase in PN levels after daily supplementation, while no increase in PN levels was detected for the other volunteers. This clearly shows that inter-individual differences in metabolism of PN exist."

"[..]it is known that women on oral contraceptives excrete increased amounts of vitamin B6 metabolites. This possibly also explains different baseline levels of PLP between the two groups prior to supplementation of either PLP or PN (Fig. 3)."

"Differences in metabolism of PN after supplementation possibly explains the individual differences in sensitivity to the neuropathic effects of vitamin B6. Hence, not only the dose, but also the vitamer present in the vitamin B6 supplements is important for the development of such adverse health effects. This is also presented by the data from Lareb, showing that more than 96% of the reports is due to the use of PN in the supplements."

 

[Debz]

Yep. And the older the person the less pyridoxine they are able to convert into P5P. That's one of the main reasons we use P5P in our Energin and not the pyrodoxine Hcl. The latter will probably work OK in people under 30 but its (neuro)toxicity becomes rather obvious with advancing age and in doses higher than 25mg daily.

Haidut, what would you recommend for my 75 year old Dad who is super fit besides having bad Peripheral neuropathy. Which he now thinks is from B6 toxicity. Besides taking benfotiamine
what else do you suggest. Although he eats healthily he did go on the keto wagon but now eats fruit and fruit juice. He also stays away from milk, will calcium help?

 

[Dr. B]

that is kind of concerning that the b6 depletes the b1, but then if you take both b1 and b6 it may be depleting something else. even taking all the bs could be depleting some mineral or other unknown nutrient... and this is all assuming you are dosing the vitamins properly in the same ratios as found in food. even that alone can be troublesome

 

[Sapien]

that is kind of concerning that the b6 depletes the b1, but then if you take both b1 and b6 it may be depleting something else. even taking all the bs could be depleting some mineral or other unknown nutrient... and this is all assuming you are dosing the vitamins properly in the same ratios as found in food. even that alone can be troublesome

Nutrition is complicated :/ lol

 

[Hitchens]

P5P over a few days made me have a panic attack at night, I imagine, the 5 ar inhibition lowers estrogen and serotonin and as I am still recovering from serotonin syndrome, I am prone to sensitivity. Pyrodoxine HCL on the other hand has been pleasant along with Taurine.

 

[Dr. B]

P5P over a few days made me have a panic attack at night, I imagine, the 5 ar inhibition lowers estrogen and serotonin and as I am still recovering from serotonin syndrome, I am prone to sensitivity. Pyrodoxine HCL on the other hand has been pleasant along with Taurine.

Pyridoxine lowers prolactin iirc...
Btw b6 should promote taurine production also I think b6 actually increases serotonin production but have to double check. Normaly cysteine and b6 work together to create taurine iirc...