What impairs vitamin B6 production/utilization?

[datadragon]

Upon further verification, my high B6 levels are not pyridoxine, but rather P5P. So it looks like it's not an activation problem.... its looks like it's just accumulating. ...
Yeah but I called the lab and my high B6 values are actually p5p, so it's already active. And I never supplemented B6

Plasma P5P (called PLP) shows an inverse relation to C-reactive protein (CRP) and other inflammatory markers, and would also potentially increase homocysteine which activates NLRP3 inflammasome when low and increase inflammatory markers. So perhaps checking c-reactive protein and homocysteine and any other indirect markers here or what your doctor may want to check might be useful https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5988249/

Participants in the highest quartile of plasma PLP had lower plasma fasting glucose and HbA1c concentrations than those in the lower quartiles. Higher plasma PLP was significantly correlated with higher HDL cholesterol So those might also be used to confirm low utilization of the high B6 or its not active. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2806890/

Mercury in nanomolar concentrations inhibits the intestinal pyridoxal kinase, activator of Vitamin B6 https://pubmed.ncbi.nlm.nih.gov/4252567/

And if it is actually P5P, perhaps the low zinc from high inflammation may also be needed for utilization of the b6. The intestinal absorption of both PNP and PMP (phosphorylated animal forms), as well as the final tissue uptake of circulating PLP requires a different enzyme that has zinc as a co-factor. Riboflavin, or vitamin B2, is needed for the phosphorylation of all forms of absorbed B6 to active PLP in the liver. Thus, poor intakes of zinc and/or riboflavin may exacerbate or lead to B6 deficiencies https://www.westonaprice.org/health...ion/vitamin-b6-the-under-appreciated-vitamin/
That might suggest trying first to lower the inflammation with NLRP3 inhibitors to allow zinc to be available to do its functions or taking a zinc amino acid form that bypasses the natural uptake issue during inflammation may help. Sounds like you may need to avoid higher B6 containing foods and supplements as well until it comes down.

 

[Outlaw]

Plasma P5P (called PLP) shows an inverse relation to C-reactive protein (CRP) and other inflammatory markers, and would also potentially increase homocysteine which activates NLRP3 inflammasome when low and increase inflammatory markers. So perhaps checking c-reactive protein and homocysteine and any other indirect markers here or what your doctor may want to check might be useful https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5988249/

Participants in the highest quartile of plasma PLP had lower plasma fasting glucose and HbA1c concentrations than those in the lower quartiles. Higher plasma PLP was significantly correlated with higher HDL cholesterol So those might also be used to confirm low utilization of the high B6 or its not active. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2806890/

Mercury in nanomolar concentrations inhibits the intestinal pyridoxal kinase, activator of Vitamin B6 https://pubmed.ncbi.nlm.nih.gov/4252567/

And if it is actually P5P, perhaps the low zinc from high inflammation may also be needed for utilization of the b6. The intestinal absorption of both PNP and PMP (phosphorylated animal forms), as well as the final tissue uptake of circulating PLP requires a different enzyme that has zinc as a co-factor. Riboflavin, or vitamin B2, is needed for the phosphorylation of all forms of absorbed B6 to active PLP in the liver. Thus, poor intakes of zinc and/or riboflavin may exacerbate or lead to B6 deficiencies https://www.westonaprice.org/health...ion/vitamin-b6-the-under-appreciated-vitamin/
That might suggest trying first to lower the inflammation with NLRP3 inhibitors to allow zinc to be available to do its functions or taking a zinc amino acid form that bypasses the natural uptake issue during inflammation may help.

Wow thanks a lot for that.

It's definitely P5P in my tests. So you're saying zinc is used in enzyme reactions AFTER conversion to P5P?

And from what I understand, B2 is used to convert to p5p, so wouldnt be a likely suspect in my case?

 

[datadragon]

Wow thanks a lot for that.

It's definitely P5P in my tests. So you're saying zinc is used in enzyme reactions AFTER conversion to P5P?

And from what I understand, B2 is used to convert to p5p, so wouldnt be a likely suspect in my case?

Yes, there are additional steps required. It appears that zinc and magnesium are cofactors needed to facilitate its entry into the cell for example so that may be why a few of you @JES may have B6 but its not being utilized rather than just not forming P5P. You can at least first test those things mentioned such as c-reactive protein, homocysteine, fasting glucose and HBA1c etc to see if its getting utilized when you take small amounts of P5P. Under inflammatory conditions zinc uptake/absorption is lowered as well as made less available for the body to utilize.

PLP cannot cross the cell membrane and circulating PLP first becomes dephosphorylated to PL by tissue-resident alkaline phosphatases, then, upon entry into the cell, all B6 forms are rapidly phosphorylated by pyridoxal kinase (PDXK). Phosphorylation captures the intracellular vitamin B6 and then a second enzyme, pyridoxine 5-phosphate oxidase (PNPO), converts PNP into the bioactive form PLP. https://www.sciencedirect.com/science/article/pii/S0022316623019326

Prior to tissue uptake, PLP is dissociated from the plasma albumin and dephosphorylated to facilitate entry into the cell. It is then rephosphorylated after cell entry. Interconversion between PLP and PMP occurs within the tissues. Transport across the cell membrane is preceded by hydrolysis of the phosphorylated B6 vitamers by membrane-bound alkaline phosphatase (ALPL). Alkaline phosphatases are a group of isoenzymes, located on the outer layer of the cell membrane; they catalyze the hydrolysis of organic phosphate esters present in the extracellular space. Zinc and magnesium are important co-factors of this enzyme. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6357176/

Interleukin-6 (IL-6) up-regulates the ZIP14 gene expression ZIP14 (Slc39a14)., which in turn, is responsible for an excess of intracellular zinc and, at the same time, for hypozincemia that accompanies the acute phase response to inflammation and infection. Infection and inflammation produce systemic responses that include hypozincemia and hypoferremia. Interleukin-6 regulates the zinc transporter Zip14 in the liver and contributes to the hypozincemia of the acute-phase response. https://www.pnas.org/doi/10.1073/pnas.0502257102

The cytokine interleukin 6 (IL6) induces the expression of Metallothionein and α2-macroglobulin (A2M) and consequently reduces zinc availability. IL-6 is released during the acute phase of an inflammatory response. This mechanism is beneficial to the acute immune response, however, a long-term decrease in zinc availability may contribute to pathological processes in conditions of chronic inflammation https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5490603/

We demonstrated that prenatal LPS exacerbates proinflammatory cytokine production in the offspring. These proinflammatory cytokines produced after LPS exposure induce metallothionein, which sequesters zinc and induces maternal and fetal hypozincemia. (Metallothionein (MT) is a zinc-binding protein that when induced in the mother's liver during the acute phase response such as infection or inflammation has been found to cause a fetal Zinc deficiency.) https://pubmed.ncbi.nlm.nih.gov/18793679/

Interferon-z (IFN-a) and inflammatory cytokines IL-1, IL-6 and TNF-a, have all been shown to induce metallothioneins (Numerous links) Type 1 interferon responses reduce plasma Zinc concentrations by inducing hepatic metallothionein expression in various model organisms (Sato et al., 1996, Guevara-Ortiz et al., 2005, Van Miert et al., 1990, Morris and Huang, 1987), as well as in human cells.

 

[Outlaw]

Yes, there are additional steps required. It appears that zinc and magnesium are cofactors needed to facilitate its entry into the cell for example so that may be why a few of you @JES may have B6 but its not being utilized rather than just not forming P5P. You can at least first test those things mentioned such as c-reactive protein, homocysteine, fasting glucose and HBA1c etc to see if its getting utilized when you take small amounts of P5P. Under inflammatory conditions zinc uptake/absorption is lowered as well as made less available for the body to utilize.

PLP cannot cross the cell membrane and circulating PLP first becomes dephosphorylated to PL by tissue-resident alkaline phosphatases, then, upon entry into the cell, all B6 forms are rapidly phosphorylated by pyridoxal kinase (PDXK). Phosphorylation captures the intracellular vitamin B6 and then a second enzyme, pyridoxine 5-phosphate oxidase (PNPO), converts PNP into the bioactive form PLP. https://www.sciencedirect.com/science/article/pii/S0022316623019326

Prior to tissue uptake, PLP is dissociated from the plasma albumin and dephosphorylated to facilitate entry into the cell. It is then rephosphorylated after cell entry. Interconversion between PLP and PMP occurs within the tissues. Transport across the cell membrane is preceded by hydrolysis of the phosphorylated B6 vitamers by membrane-bound alkaline phosphatase (ALPL). Alkaline phosphatases are a group of isoenzymes, located on the outer layer of the cell membrane; they catalyze the hydrolysis of organic phosphate esters present in the extracellular space. Zinc and magnesium are important co-factors of this enzyme. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6357176/

Interleukin-6 (IL-6) up-regulates the ZIP14 gene expression ZIP14 (Slc39a14)., which in turn, is responsible for an excess of intracellular zinc and, at the same time, for hypozincemia that accompanies the acute phase response to inflammation and infection. Infection and inflammation produce systemic responses that include hypozincemia and hypoferremia. Interleukin-6 regulates the zinc transporter Zip14 in the liver and contributes to the hypozincemia of the acute-phase response. https://www.pnas.org/doi/10.1073/pnas.0502257102

The cytokine interleukin 6 (IL6) induces the expression of Metallothionein and α2-macroglobulin (A2M) and consequently reduces zinc availability. IL-6 is released during the acute phase of an inflammatory response. This mechanism is beneficial to the acute immune response, however, a long-term decrease in zinc availability may contribute to pathological processes in conditions of chronic inflammation https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5490603/

We demonstrated that prenatal LPS exacerbates proinflammatory cytokine production in the offspring. These proinflammatory cytokines produced after LPS exposure induce metallothionein, which sequesters zinc and induces maternal and fetal hypozincemia. (Metallothionein (MT) is a zinc-binding protein that when induced in the mother's liver during the acute phase response such as infection or inflammation has been found to cause a fetal Zinc deficiency.) https://pubmed.ncbi.nlm.nih.gov/18793679/

Interferon-z (IFN-a) and inflammatory cytokines IL-1, IL-6 and TNF-a, have all been shown to induce metallothioneins (Numerous links) Type 1 interferon responses reduce plasma Zinc concentrations by inducing hepatic metallothionein expression in various model organisms (Sato et al., 1996, Guevara-Ortiz et al., 2005, Van Miert et al., 1990, Morris and Huang, 1987), as well as in human cells.

Super interesting thanks!!

Should I be worried about nerve damage from high B6? My OAT showed deficiency for functional B6 markers, so I think it looks like mis-utilization rather than excess... so I shouldnt be concerned about nerve damage?

 

[datadragon]

Should I be worried about nerve damage from high B6? My OAT showed deficiency for functional B6 markers, so I think it looks like mis-utilization rather than excess... so I shouldnt be concerned about nerve damage?

According to this research it appears to be the pyridoxine form that causes the main problems such as neuropathy/nerve damage after taking a relatively high dose of pyridoxine supplements, and more so I'm sure when that person is further unable to convert it allowing those levels to remain at high levels. Also further competitively inhibiting the active P5P form as well causing a functional deficiency. https://www.sciencedirect.com/science/article/abs/pii/S0887233317301959?via=ihub All this info on utilization is new. Im not sure if high P5P that is not getting into the cell and being utilized can cause those issues also to some degree, but at the level you mentioned you should be experiencing those problems now if it were I would imagine. I would certainly try to see someone like a neurologist if possible and test your c-reactive protein and other mentioned ways to try to help confirm its P5P and not getting utilized, work on reducing any intake of b6 since its extremely high, and perhaps considering with your medical practitioner something like zinc amino acids and magnesium which says it might help to start to utilize it, bring levels down which may also lessen the need for other anti inflammatory things. A neurologist can also test nerves if you are experiencing those issues.

There is a like next to quote by the way you can like posts which notifies people in addition to when you quote them or tag them such as @datadragon . Otherwise I may not see when someone replied without one of those in the message.

 

[Outlaw]

@datadragon

Ok I see thanks a lot for the help, I appreciate it so much, I'll try to get the creactive protein test!

Yeah, I am at 317 (range 20-90) in my latest test. I do eat a lot of chicken (like almost 1kg per day), but I dont think it would cause that. I will also try b2/b3/boron/zinc, as they all can help utilization apparently.

Also, I read that candida can prevent b6 utilization. I did have really high arabinose on my OAT (and other candida markers), and I do have dysbiosis

 

[datadragon]

Yeah, I am at 317 (range 20-90) in my latest test. I do eat a lot of chicken (like almost 1kg per day), but I dont think it would cause that. I will also try b2/b3/boron/zinc, as they all can help utilization apparently.

Also, I read that candida can prevent b6 utilization. I did have really high arabinose on my OAT (and other candida markers), and I do have dysbiosis

Leaky gut is also another side effect of zinc deficiency (or unavailability as per the above info I posted) and happens during inflammation/infection. The other nutrients you mentioned (b2/b3/boron/zinc) are all anti-inflammatory so its probably a good idea to adjust taking those and any others with anti inflammatory properties based on your inflammation levels which require balance. If you can lower the inflammation when high that also may help allow zinc to be able to be utilized better if that is contributing to the problem as suggested by the research. Good luck.

 

[Outlaw]

Leaky gut is also another side effect of zinc deficiency (or unavailability as per the above info I posted) and happens during inflammation/infection. The other nutrients you mentioned (b2/b3/boron/zinc) are all anti-inflammatory so its probably a good idea to adjust taking those and any others with anti inflammatory properties based on your inflammation levels which require balance. If you can lower the inflammation when high that also may help allow zinc to be able to be utilized better if that is contributing to the problem as suggested by the research. Good luck.

Thanks chief I'll try that in the next weeks, will report back

 

[lowALP]

Just to add on to what was said above, alkaline phosphatase (ALP from typical liver panel blood work) is necessary to utilize PLP. Persistently low ALP + high B6 (like 10-100x) is hallmark of hypophosphatasia. There is debate about whether or not there is a functional B6 deficiency. I have persistently low ALP (upper 20s, lower ref range is 30 or 40) and have seen an endocrinologist and have appointment for genetic test, though my B6 is normal range. Hopefully your ALP is normal. BTW, taking Ca/Mg butyrate supplement does wonders for gut health. I stopped taking it for a few weeks and issues returned. Good bacteria are supposed to make this to feed gut and replacing it helps immensely. It can be used to make GABA so is best to take in evening.

 

[datadragon]

Just to add on to what was said above, alkaline phosphatase (ALP from typical liver panel blood work) is necessary to utilize PLP. Persistently low ALP + high B6 (like 10-100x) is hallmark of hypophosphatasia.

Correct. The Alkaline Phosphatase (ALPL) Locus Is Associated with B6 Vitamer Levels in CSF and Plasma. Transport across the cell membrane is preceded by hydrolysis of the phosphorylated B6 vitamers by membrane-bound alkaline phosphatase (ALPL) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6357176/

Hypophosphatasia is normally due to genetic mutations of the tissue non-specific alkaline phosphatase (TNSALP) however Zinc is a cofactor of TNSALP and so as mentioned before its usually due to zinc unavailability or deficiency that leads to problems with active B6 utilization beyond just its convesion to the active form so taking active form b6 still may not work properly in a high inflammation/infection state in the presence of pro inflammatory cytokines. https://www.sciencedirect.com/science/article/pii/S8756328223001825

It can be used to make GABA so is best to take in evening.

L-Glutamic acid decarboxylase is the major enzyme in the synthesis of g-amino butyric acid (GABA) which is a potent inhibitory neurotransmitter. It requires a co-factor, pyridoxal 5’-phosphate (i.e. (PLP or activated vitamin B6] to catalyze this reaction. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3411186/ and https://en.wikipedia.org/wiki/Glutamate_decarboxylase Separate from that lactobacillus reuteri which is lowered from zinc deficiency (due to lowering shank3 levels) is correlated with GABA in the brain. Lactobacillus reuteri, a species with decreased relative abundance in the Shank3 KO mice, positively correlated with the expression of gamma-Aminobutyric acid (GABA) receptor subunits in the brain. https://forums.phoenixrising.me/thr...-on-right-side-may-be-best.89827/post-2441279