Vitamin B6 (P5P) Is A Glucocorticoid (cortisol) Antagonist

Discussion in 'Scientific Studies' started by haidut, Feb 24, 2015.

  1. haidut

    haidut Member

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    The studies go back to 1960s and 1970s but when I read them I was surprised to find that the activated form of vitamin B6 called pyridoxal-5-phosphate (what we also use for our Energin supplement) is a glucocorticoid "receptor" antagonist. Some of the in vivo studies referenced in the studies posted below show clear reduction in serum cortisol as well as reversal of conditions caused by high cortisol (e.g. stress ulcer, metabolic syndrome, etc.). In addition, the older studies discuss something called Syndrome X (metabolic syndrome) and its common characteristics of belly fat and insulin resistance. According to those studies, the metabolic syndrome is directly caused by increased fetal exposure to cortisol during pregnancy, which results in decreased cortisol sensitivity and thus chronically elevated cortisol levels during adulthood. Vitamin B6 was able to reverse this condition (in animals).
    Combined with my other thread showing vitamin B6 also reduces adrenalin, it looks like the vitamin could be a good anti-stress substance for those not willing to use pharma drugs like clonidine. In addition, some of the references in the studies below show that B6 is also an estrogen "receptor" antagonist, so it could be a good addition for lowering estrogen. The human equivalent dose for preventing and reversing stress ulcers was in the range 5mg-10mg, which is within the limits that Ray recommends. Higher doses may be necessary for other conditions such as reversal of Syndrome X (metabolic syndrome). I posted a separate thread on vitamin B6 studies for glucose control and insulin sensitivity, so please refer to that thread for some human dosages.

    My previous thread on vitamin B6 and adrenalin.
    viewtopic.php?f=75&t=3245&p=46146

    http://www.ncbi.nlm.nih.gov/pubmed/10859692
    "...Since pyridoxal phosphate is a safe physiological antagonist of glucocorticoid activity, it is proposed that prenatal supplementation with high-dose pyridoxine may counteract the adverse impact of glucocorticoids on fetal growth, as well as on subsequent cardiovascular risk...Of direct relevance to this proposal are reports that supplemental pyridoxine protects fetal mice from cortisone-induced cleft palate (44,45). Glucocorticoids induce cleft palate by inhibiting palatal mesenchymal growth at a critical phase; the sensitivity of mice to this effect is proportionate to the expression of palatal glucocorticoid receptors (46). In pregnant mice eating a normal diet (10 mg/kg pyridoxine), 125 mg/kg cortisone induced cleft palate in 68% of the offspring; adding pyridoxine to drinking water at 100–500 mg/L reduced the incidence of cortisone-induced cleft palate to less than 30%. When pregnant mice were fed a pyridoxine-depleted diet, a cortisone dose of 62.5 mg/kg induced cleft palate in 63% of the newborn mice. When mice receiving the same dose of cortisone were provided with pyridoxine-enriched drinking water, the subsequent incidence of cleft palate was only 8%. This constitutes direct evidence that feasible supplemental intakes of pyridoxine can protect fetuses from the pathogenic impact of excess glucocorticoid activity. Other reports suggest that pyridoxine supplements can down-regulate endogenous glucocorticoid activity: pyridoxine can prevent restraint stress-induced gastric ulceration in rats (47), and alleviates stress induced immunosuppression in humans (48).

    It looks like only the activated form of B6 called P5P is able to modulate the glucocorticoid receptor. However, supplementing regular pyridoxine hydrochloride does raise P5P levels in humans even though the conversion factors vary wildly and in some people the conversion is almost entirely blocked. So, in people with conditions like insulin resistance or diabetes, direct supplementation with P5P may be necessary.

    http://www.ncbi.nlm.nih.gov/pubmed/7472680
    "...We further found that preincubation of the nuclear extract from the vitamin-deficient liver with pyridoxal 5'-phosphate brought about a rapid and extensive decrease in the binding of the extract to the glucocorticoid-responsive element. Congeners of pyridoxal phosphate, such as pyridoxamine 5'-phosphate, pyridoxal, pyridoxamine and pyridoxine, did not show an inhibitory effect. These observations suggest that pyridoxal 5'-phosphate modulates cAST gene expression by inactivating the binding activity of glucocorticoid receptor to glucocorticoid-responsive elements."

    Some additional studies on vitamin B6 and modulation of glucocorticoid and steroid (estrogen, progesterone, androgen) "receptors".
    http://www.ncbi.nlm.nih.gov/pubmed/8143940
    http://www.ncbi.nlm.nih.gov/pubmed/2373699
    http://www.ncbi.nlm.nih.gov/pubmed/2192624
    http://www.karger.com/Article/Abstract/177874
     
  2. Pet Peeve

    Pet Peeve Member

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    After reading the two posts I took 150 mg of pyridoxine and 50 mg p-5-p at the same time for three days in a row, once a day. This caused my temperature to drop and I became mildly lethargic and got sleepy again after eating for the first time since I started this diet. It feels like I'm going to have a cold but it doesn't come. I attribute this to the cortisol and adrenaline lowering from the B6 doses. Is it unhealthy to continue these doses in my present state? Should I increase/fix my metabolism more before continuing with these doses of B6, or is it just good to have my true stresshormone-free state revealed to me? (gauging progress etc.)

    Appreciate your help.
     
  3. OP
    haidut

    haidut Member

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    Unless you also boost thyroid, lowering the stress hormones can have a very unpleasant effects that leaves you feeling like a "zombie", as several people have reported on the forum. The point is not to just lower the stress hormones. It is also to boost thyroid function and have it be the primary driver of metabolism.
    Long term vitamin B6 is probably best kept under 10mg daily. It is enough to restrain cortisol and estrogen.
     
  4. mayweatherking

    mayweatherking Member

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    How are u ensuring you are getting enough if.these b vitamins in your diet haidut?
     
  5. OP
    haidut

    haidut Member

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    I take Energin when feeling under chronic stress. Other than that, as estrogenic as it is - beer is a great source of B vitamins, so having a pint every now and then probably provides enough to make a difference. In the summer when more fresh food is available I don't feel the need to supplement the B vitamins.
     
  6. mayweatherking

    mayweatherking Member

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    Interesting.. thought you would say liver or muscle meat. ive been researchibg online and seeing that bacteria provide enough b vitamins but they require adequate levels of vitamin D to work properly. I notice I need beef or liver now. its just interesting stuff considering rays anti bacteria in the gut viewpoints.
     
  7. tomisonbottom

    tomisonbottom Member

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    Do you know if it's problematic to take 70mg of B6 once a week vs 10 mg daily?
     
  8. OP
    haidut

    haidut Member

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    Potentially yes. Too high of a dose in a single day can lead to overstimulation and insomnia.
     
  9. aguilaroja

    aguilaroja Member

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    My experience is that B6 (P5P/PLP) supplementation effects are varied, and depend on context even more than many supports. It matches reasoning about PLP being a cofactor both in neurotransmitter and transaminase activity.
    Vitamin B6 - Wikipedia

    @haidut mentioned some possibilities for problems which may arise with even transient B6 supplementing.

    A recent short term study observed an interesting outcome-improved dream recall-which also may depend significantly on the recent metabolism of the subjects. The poorer sleep quality with B-complex (compared with B6) may coincide with different effects of different B vitamin components that @haidut and others have discussed on the forum.

    Effects of Vitamin B6 (Pyridoxine) and a B Complex Preparation on Dreaming and Sleep. - PubMed - NCBI
    "We conducted a randomized, double-blind, placebo-controlled investigation of the effects on dreaming and sleep of ingesting 240 mg vitamin B6 (pyridoxine hydrochloride) before bed for five consecutive days. We also included an exploratory condition involving a B complex preparation containing a range of B vitamins."
    "...vitamin B6 significantly increased the amount of dream content participants recalled but did not...significantly affect other sleep-related variables. In contrast, participants in the B complex group showed significantly lower self-rated sleep quality and significantly higher tiredness on waking."
     
  10. LeeLemonoil

    LeeLemonoil Member

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    The chaperone role of the pyridoxal 5'-phosphate and its implications for rare diseases involving B6-dependent enzymes.

    Cellini B1, Montioli R2, Oppici E2, Astegno A3, Voltattorni CB2.
    Author information
    Abstract

    The biologically active form of the B6 vitamers is pyridoxal 5'-phosphate (PLP), which plays a coenzymatic role in several distinct enzymatic activities ranging from the synthesis, interconversion and degradation of amino acids to the replenishment of one-carbon units, synthesis and degradation of biogenic amines, synthesis of tetrapyrrolic compounds and metabolism of amino-sugars. In the catalytic process of PLP-dependent enzymes, the substrate amino acid forms a Schiff base with PLP and the electrophilicity of the PLP pyridine ring plays important roles in the subsequent catalytic steps. While the essential role of PLP in the acquisition of biological activity of many proteins is long recognized, the finding that some PLP-enzymes require the coenzyme for refolding in vitro points to an additional role of PLP as a chaperone in the folding process. Mutations in the genes encoding PLP-enzymes are causative of several rare inherited diseases. Patients affected by some of these diseases (AADC deficiency, cystathionuria, homocystinuria, gyrate atrophy, primary hyperoxaluria type 1, xanthurenic aciduria, X-linked sideroblastic anaemia) can benefit, although at different degrees, from the administration of pyridoxine, a PLP precursor. The effect of the coenzyme is not limited to mutations that affect the enzyme-coenzyme interaction, but also to those that cause folding defects, reinforcing the idea that PLP could play a chaperone role and improve the folding efficiency of misfolded variants. In this review, recent biochemical and cell biology studies highlighting the chaperoning activity of the coenzyme on folding-defective variants of PLP-enzymes associated with rare diseases are presented and discussed.

    [​IMG]


    Med Hypotheses. 2014
    Morton's foot and pyridoxal 5'-phosphate deficiency: genetically linked traits.

    Abstract
    Vitamin B6 is an essential vitamin needed for many chemical reactions in the human body. It exists as several vitamins forms but pyridoxal 5'-phosphate (PLP) is the phosphorylated form needed for transamination, deamination, and decarboxylation. PLP is important in the production of neurotransmitters, acts as a Schiff base and is essential in the metabolism of homocysteine, a toxic amino acid involved in cardiovascular disease, stroke, thrombotic and Alzheimer's disease. This report announces the connection between a deficit of PLP with a genetically linked physical foot form known as the Morton's foot. Morton's foot has been associated with fibromyalgia/myofascial pain syndrome. Another gene mutation methylenetetrahydrofolate reductase (MTHFr) is now being recognized much commonly than previous with chronic fatigue, chronic Lyme diseases and as "the missing link" in other chronic diseases. PLP deficiency also plays a role in impaired glucose tolerance and may play a much bigger role in the obesity, diabetes, fatty liver and metabolic syndrome. Without the Schiff-base of PLP acting as an electron sink, storing electrons and dispensing them in the mitochondria, free radical damage occurs! The recognition that a phenotypical expression (Morton's foot) of a gene resulting in deficiency of an important cofactor enzyme pyridoxal 5'-phosphate will hopefully alert physicians and nutritionist to these phenomena. Supplementation with PLP, L5-MTHF, B12 and trimethylglycine should be used in those patients with hyperhomocysteinemia and/or MTHFR gene mutation.
     
  11. Antonello

    Antonello Member

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    @haidut do you think is more effective take a single dose of B6 or spread throughout the day?
     
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