Vitamin B6 deficiency disrupts serotonin signaling in pancreatic islets and induces gestational diabetes in mice.

In pancreatic islets, catabolism of tryptophan into serotonin and serotonin receptor 2B (HTR2B) activation is crucial for ß-cell proliferation and maternal glucose regulation during pregnancy. Factors that reduce serotonin synthesis and perturb HTR2B signaling are associated with decreased ß-cell number, impaired insulin secretion, and gestational glucose intolerance in mice. Albeit the tryptophan-serotonin pathway is dependent on vitamin B6 bioavailability, how vitamin B6 deficiency impacts ß-cell proliferation during pregnancy has not been investigated. In this study, we created a vitamin B6 deficient mouse model and investigated how gestational deficiency influences maternal glucose tolerance. Our studies show that gestational vitamin B6 deficiency decreases serotonin levels in maternal pancreatic islets and reduces ß-cell proliferation in an HTR2B-dependent manner. These changes were associated with glucose intolerance and insulin resistance, however insulin secretion remained intact. Our findings suggest that vitamin B6 deficiency-induced gestational glucose intolerance involves additional mechanisms that are complex and insulin independent.

The regulatory effects of pyridoxine deficiency on the grass carp (Ctenopharyngodon idella) gill barriers immunity, apoptosis, antioxidant, and tight junction challenged with Flavobacterium columnar.

The effects of dietary pyridoxine (PN) on the gill immunity, apoptosis, antioxidant and tight junction of grass cap (Ctenopharyngodon idella) were investigated in this study. Fish were fed semi-purified diets containing graded levels of PN for 10 weeks, and then challenged with Flavobacterium columnare by bath immersion exposure for 3 days. The results indicated that compared with the optimal PN level, PN deficiency resulted in a decline in the antimicrobial compound production of gill. In addition, PN deficiency up-regulated the pro-inflammatory cytokines and down-regulated the anti-inflammatory cytokines gene expression, which might be associated with the enhanced nuclear factor κB p65 and the inhibited target of rapamycin signalling pathways, respectively, suggesting that PN deficiency could impair gill immune barrier function. Furthermore, PN deficiency (1) induced cell apoptosis, which may be partly associated with the (apoptotic protease activating factor-1, Bcl-2 associated X protein)/caspase-9 and c-Rel/tumor necrosis factor α (rather than FasL)/caspase-8 mediated apoptosis pathway. (2) Inhibited Kelch-like ECH-associating protein 1a/NF-E2-related factor 2 mRNA expression, decreased the mRNA expression and activities of antioxidant enzymes, increased the levels of reactive oxygen species, protein carbonyl and malondialdehyde. (3) Increased the mRNA expression level of myosin light chain kinase, which may be result in the down-regulation of tight junction complexes such as zonula occludens 1, occludin and claudins (expect claudin-12 and claudin-15). These results suggest that PN deficiency could impair gill physical barrier function. In summary, dietary PN deficiency could cause the impairment of gill barrier function associated with immunity, apoptosis, antioxidant and tight junction, which may result in the increased the susceptibility of fish to pathogenic bacteria. Moreover, based on the gill rot morbidity, LZ activity and MDA content, the dietary PN requirements for grass cap were estimated to be 4.85, 4.78 and 4.77 mg kg-1 diet, respectively.

Insight into vitamin B6 -dependent epilepsy due to PLPBP (previously PROSC) missense mutations.

Vitamin B6 -dependent genetic epilepsy was recently associated to mutations in PLPBP (previously PROSC), the human version of the widespread COG0325 gene that encodes TIM-barrel-like pyridoxal phosphate (PLP)-containing proteins of unclear function. We produced recombinantly, purified and characterized human PROSC (called now PLPHP) and its six missense mutants reported in epileptic patients. Normal PLPHP is largely a monomer with PLP bound through a Schiff-base linkage. The PLP-targeting antibiotic d-cycloserine decreased the PLP-bound peak as expected for pseudo-first-order reaction. The p.Leu175Pro mutation grossly misfolded PLPHP. Mutations p.Arg241Gln and p.Pro87Leu decreased protein solubility and yield of pure PLPHP, but their pure forms were well folded, similarly to pure p.Pro40Leu, p.Tyr69Cys, and p.Arg205Gln mutants (judged from CD spectra). PLPHP stability was decreased in p.Arg241Gln, p.Pro40Leu, and p.Arg205Gln mutants (thermofluor assays). The p.Arg241Gln and p.Tyr69Cys mutants respectively lacked PLP or had a decreased amount of this cofactor. With p.Tyr69Cys there was extensive protein dimerization due to disulfide bridge formation, and PLP accessibility was decreased (judged from d-cycloserine reaction). A 3-D model of human PLPHP allowed rationalizing the effects of most mutations. Overall, the six missense mutations caused ill effects and five of them impaired folding or decreased stability, suggesting the potential of pharmacochaperone-based therapeutic approaches.

Vitamin B-6, Independent of Homocysteine, Is a Significant Factor in Relation to Inflammatory Responses for Chronic Kidney Disease and Hemodialysis Patients.

The purpose of this study was to investigate whether plasma pyridoxal 5'-phosphate (PLP) and homocysteine were dependent on or independent of each other in order to be associated with inflammatory markers in patients with chronic kidney disease (CKD) or those receiving hemodialysis treatment. This was a cross-sectional study. Sixty-eight stage 2-5 CKD patients and 68 hemodialysis patients had one time fasting blood drawn for measurements of plasma PLP, pyridoxal (PL), homocysteine, and several inflammatory markers. Early CKD stage (stages 2-3) patients showed significantly lower plasma PLP levels and homocysteine concentrations than patients in an advanced CKD stage (stages 4-5) and those undergoing hemodialysis. Plasma PLP significantly correlated with CRP levels (partial rs = -0.21, p < 0.05) and plasma PL significantly correlated with IL-10 levels (partial rs = -0.24, p < 0.01), while plasma PLP plus PL significantly correlated with both CRP levels (partial rs = -0.20, p < 0.05) and interleukin-1ß (partial rs = 0.22, p < 0.05) levels after adjusting for plasma homocysteine and other potential confounders. Plasma homocysteine displayed no significant correlations with any inflammatory markers. Vitamin B-6 status, rather than homocysteine, appeared to be a significant factor in relation to inflammatory responses for CKD and hemodialysis patients.

Plasma folate, vitamin B-6, and vitamin B-12 and breast cancer risk in BRCA1- and BRCA2-mutation carriers: a prospective study.

BACKGROUND: B vitamins [vitamins B-6, B-9 (folate), and B-12] play important roles in nucleotide biosynthesis and biological methylation reactions, aberrancies of which have all been implicated in carcinogenesis. In the general population, evidence has suggested that high circulating folate and folic acid (synthetic form of folate) supplement use may increase breast cancer risk, but the role of folate in BRCA-associated breast cancer is not clear. OBJECTIVE: We prospectively evaluated the relation between plasma folate, pyridoxal 5'-phosphate (PLP; the biologically active form of vitamin B-6), and vitamin B-12 and breast cancer risk in women with a BRCA1/2 mutation. DESIGN: Baseline blood samples and biennial follow-up questionnaires were available for 164 BRCA1/2-mutation carriers with no previous history of cancer other than nonmelanoma skin cancer. Plasma folate, PLP, and vitamin B-12 concentrations were categorized dichotomously as high compared with low based on the upper 25% and the lower 75% of distribution, respectively. Cox proportional hazards were used to estimate the HR and 95% CI for the association between plasma biomarkers of each B vitamin and incident breast cancer. RESULTS: Over a mean follow-up of 6.3 y, 20 incident primary invasive breast cancers were observed. Women with high plasma folate concentrations (>24.4 ng/mL) were associated with significantly increased breast cancer risk (HR: 3.20; 95% CI: 1.03, 9.92; P = 0.04, P-trend across quintiles = 0.07) compared with that of women with low plasma folate concentrations (≤24.4 ng/mL). Plasma PLP and vitamin B-12 concentrations were not associated with breast cancer risk. CONCLUSIONS: Our data suggest that elevated plasma folate concentrations may be associated with increased risk of breast cancer in women with a BRCA1/2 mutation. Additional studies with a larger sample size and longer follow-up periods are warranted to clarify the relation between folate status and breast cancer risk in high-risk women.

Oral exposure to the anti-pyridoxine compound 1-amino D-proline further perturbs homocysteine metabolism through the transsulfuration pathway in moderately vitamin B6 deficient rats.

Pyridoxal 5'-phosphate (PLP; a B6 vitamer) serves as an important cofactor in a myriad of metabolic reactions, including the transsulfuration (TS) pathway, which converts homocysteine (Hcy) to cysteine. While overt vitamin B6 deficiency is rare, moderate deficiency is common and may be exacerbated by anti-pyridoxine factors in the food supply. To this end, we developed a model of moderate B6 deficiency and a study was conducted to examine the in vivo effect of 1-amino D-proline (1ADP), an anti-pyridoxine factor found in flaxseed, on indices of Hcy metabolism through the TS pathway in moderately B6 deficient rats. Male weaning rats received a semi-purified diet containing either 7 mg/kg (control; CD) or 0.7 mg/kg (moderately deficient; MD) diet of pyridoxine·hydrochloride (PN∙HCl), each with 1 of 4 levels of 1ADP, viz. 0, 0.1, 1 and 10 mg/kg diet for 5 weeks. Perturbations in vitamin B6 biomarkers were more pronounced in the MD group. Plasma PLP was significantly reduced, while plasma Hcy (8-fold) and cystathionine (11-fold) were increased in rats consuming the highest amount of 1ADP in the MD group. The activities of hepatic cystathionine ß-synthase and cystathionine γ-lyase enzymes were significantly reduced in rats consuming the highest 1ADP compared to the lowest, for both levels of PN∙HCl. Dilation of hepatic central veins and sinusoids, mild steatosis and increased liver triglycerides were present in MD rats consuming the highest 1ADP level. The current data provide evidence that the consumption of an anti-pyridoxine factor linked to flaxseed may pose a risk for subjects who are moderate/severe vitamin B6 deficient.

Vitamin B-6 restriction reduces the production of hydrogen sulfide and its biomarkers by the transsulfuration pathway in cultured human hepatoma cells.

BACKGROUND: Pyridoxal 5'-phosphate (PLP) functions as a coenzyme in many cellular processes including one-carbon metabolism and the interconversion and catabolism of amino acids. PLP-dependent enzymes, cystathionine ß-synthase and cystathionine γ-lyase, function in transsulfuration but also have been implicated in the production of the endogenous gaseous signaling molecule hydrogen sulfide (H2S) concurrent with the formation of the biomarkers lanthionine and homolanthionine. OBJECTIVE: Our objective was to determine if H2S production and concurrent biomarker production is affected by vitamin B-6 restriction in a cell culture model. METHODS: We used cultured human hepatoma cells and evaluated static intracellular profiles of amino acids and in vivo kinetics of H2S biomarker formation. Cells were cultured for 6 wk in media containing concentrations of pyridoxal that represented severe vitamin B-6 deficiency (15 nmol/L pyridoxal), marginal deficiency (56 nmol/L pyridoxal), adequacy (210 nmol/L pyridoxal), and standard medium formulation providing a supraphysiologic pyridoxal concentration (1800 nmol/L pyridoxal). RESULTS: Intracellular concentrations of lanthionine and homolanthionine in cells cultured at 15 nmol/L pyridoxal were 50% lower (P < 0.002) and 47% lower (P < 0.0255), respectively, than observed in cells cultured at 1800 nmol/L pyridoxal. Extracellular homocysteine and cysteine were 58% and 46% higher, respectively, in severely deficient cells than in adequate cells (P < 0.002). Fractional synthesis rates of lanthionine (P < 0.01) and homolanthionine (P < 0.006) were lower at 15 and 56 nmol/L pyridoxal than at both higher pyridoxal concentrations. The rate of homocysteine remethylation and the fractional rate of homocysteine production from methionine were not affected by vitamin B-6 restriction. In vitro studies of cell lysates using direct measurement of H2S also had a reduced extent of H2S production in the 2 lower vitamin B-6 conditions. CONCLUSION: In view of the physiologic roles of H2S, these results suggest a mechanism that may be involved in the association between human vitamin B-6 inadequacy and its effects on human health.

A history of the isolation and identification of vitamin B(6).

In the 1930s, Rudolf Peters showed that young rats kept on a semi-synthetic diet with added thiamin and riboflavin but no other supplement developed 'rat acrodynia', a condition characterized by severe cutaneous lesions. In 1934, Paul György showed that the factor which cured 'rat acrodynia' was vitamin B(6). Other studies soon showed that vitamin B(6) deficiency produced convulsions in rats, pigs, and dogs, and a microcytic anemia in certain animals. Samuel Lepkovsky isolated and crystallized vitamin B(6) in 1938. The following year, Leslie Harris and Karl Folkers, and Richard Kuhn and his associates independently showed that vitamin B(6) was a pyridine derivative, 3-hydroxy-4,5-dihydroxy-methyl-2-methyl-pyridine. György proposed the term pyridoxine for this derivative. Esmond Snell developed a microbiological growth assay in 1942 that led to the characterization of pyridoxamine, the animated product of pyridoxine, and pyridoxal, the formyl derivative of pyridoxine. Further studies showed that pyridoxal, pyridoxamine, and pyridoxine have largely equal activity in animals and owe their vitamin activity to the ability of the organism to convert them into the enzymatically active form pyridoxal-5-phosphate. Pyridoxal-5-phosphate plays a role in a wide variety of enzyme systems, especially in the metabolic utilization and transformation of amino acids.

Marginal vitamin B-6 deficiency decreases plasma (n-3) and (n-6) PUFA concentrations in healthy men and women.

Previous animal studies showed that severe vitamin B-6 deficiency altered fatty acid profiles of tissue lipids, often with an increase of linoleic acid and a decrease of arachidonic acid. However, little is known about the extent to which vitamin B-6 deficiency affects human fatty acid profiles. The aim of this study was to determine the effects of marginal vitamin B-6 deficiency on fatty acid profiles in plasma, erythrocytes, and peripheral blood mononuclear cells (PBMC) of healthy adults fed a 28-d, low-vitamin B-6 diet. Healthy participants (n = 23) received a 2-d, controlled, vitamin B-6-adequate diet followed by a 28-d, vitamin B-6-restricted diet to induce a marginal deficiency. Plasma HDL and LDL cholesterol concentrations, FFA concentrations, and erythrocyte and PBMC membrane fatty acid compositions did not significantly change from baseline after the 28-d restriction. Plasma total arachidonic acid, EPA, and DHA concentrations decreased from (mean ± SD) 548 ± 96 to 490 ± 94 µmol/L, 37 ± 13 to 32 ± 13 µmol/L, and 121 ± 28 to 109 ± 28 µmol/L [positive false discovery rate (pFDR) adjusted P < 0.05], respectively. The total (n-6):(n-3) PUFA ratio in plasma exhibited a minor increase from 15.4 ± 2.8 to 16.6 ± 3.1 (pFDR adjusted P < 0.05). These data indicate that short-term vitamin B-6 restriction decreases plasma (n-3) and (n-6) PUFA concentrations and tends to increase the plasma (n-6):(n-3) PUFA ratio. Such changes in blood lipids may be associated with the elevated risk of cardiovascular disease in vitamin B-6 insufficiency.

Oral contraceptive use: impact on folate, vitamin B6, and vitamin B12 status.

Since many unplanned pregnancies occur while women are using oral contraceptives (OCs), it is important to understand the potential impact of these drugs on folate, vitamin B6 , and vitamin B12 status. Although a number of early studies concluded that OCs negatively impact folate status, the majority of these studies were conducted when the estrogen content of OCs was much higher. In addition, the interpretation of findings from many of these studies is problematic since no controls were included for potentially confounding factors. The presently available data do not support a conclusion that currently used OCs negatively impact folate status. In regard to vitamin B6 , however, existing population-based data do provide evidence that current low-dose OCs may negatively impact vitamin B6 status. The observed depression in plasma pyridoxal 5'-phosphate concentrations in OC users may reflect decreased body reserves of the vitamin, which could put women who discontinue OCs and become pregnant at risk for vitamin B6 inadequacy during pregnancy. Functional indicators of vitamin B12 status are not significantly impacted by OC use. Definitive conclusions, however, await further investigations.

Pyridoxine supply in human development.

Vitamin B(6) has an important role in the function of the human nervous system. Experimental data are not generally available on the role in human development, but significant conclusions may be made from studies of the effect of disorders of B(6) vitamer metabolism. Vitamin B(6) comprises seven compounds - pyridoxal, pyridoxine, pyridoxamine and their respective 5' phosphates. The common active form in human tissue is the 5'-phosphate form of pyridoxal (PLP) most of which is found in muscle bound to phosphorylase. Like many vitamins, B(6) can function both as a co-enzyme and as a chaperone. Pyridoxal-5'-phosphate is the metabolically active form and is involved in 100 enzymatic reactions including carbohydrate, amino acid, and fatty acid metabolism. There is evidence that in some situations B(6) vitamers can function as antioxidants. The fetus is dependent on the placenta for supply of vitamin B(6) and the demand correlates with amino acid metabolism. Few reports are available on the role of B(6) in embryogenesis. Studies of human disorders where B(6) metabolism is blocked show a major role in neurotransmitter function with secondary cerebral and cerebellar hypoplasia. Pyridoxine potentiates vitamin A teratogenicity and an excess leads to peripheral nerve cell degeneration. The key role of vitamin B(6) in the developing human is in metabolism, especially of the neurotransmitters.

Vitamin B6 suppresses serine protease inhibitor 3 expression in the colon of rats and in TNF-α-stimulated HT-29 cells.

SCOPE: Previous reports in the areas of animal studies and, recently epidemiology, have linked anti-tumorigenic and anti-inflammatory effects to dietary vitamin B6. This study investigated the molecular mechanism of these effects of vitamin B6. METHODS AND RESULTS: DNA microarray analysis was used to obtain information on changes in colon gene expression from vitamin B6 (pyridoxine) repletion in vitamin B6-deficient rats. Pyridoxine supplementation down-regulated the inflammatory molecule, serine protease inhibitor clade A member 3 (SPI-3) mRNA expression in the colon. This study also showed that tumor necrosis factor α (TNF-α) induced SPI-3 mRNA expression in HT-29 human colon cancer cells, and vitamin B6 (pyridoxal hydrochloride) pretreatment of HT-29 cells inhibited TNF -induced mRNA expression of SPI-3. Vitamin B6 inhibited TNF-α-induced NF-κB activation via suppression of IκBα degradation in HT-29 cells. HT-29 cells stably expressing epitope-tagged ubiquitin were generated and vitamin B6 pretreatment was shown to inhibit ubiquitination of the IkB protein in response to TNF-α-i. CONCLUSION: Vitamin B6 suppressed SPI-3 expression in the colon of rats and in TNF-α-stimulated HT-29 cells. Further, this study showed a possible role of vitamin B6 in the regulation of protein ubiquitination.

Vitamin B-6 restriction tends to reduce the red blood cell glutathione synthesis rate without affecting red blood cell or plasma glutathione concentrations in healthy men and women.

BACKGROUND: Glutathione plays various protective roles in the human body. Vitamin B-6 as pyridoxal-5'-phosphate (PLP) is required as the coenzyme in the formation of glutathione precursors. Despite this obligatory role of PLP, previous studies from this laboratory showed that vitamin B-6 deficiency caused elevated glutathione concentrations in rat liver and human plasma. OBJECTIVE: Our aim was to determine the effect of marginal vitamin B-6 deficiency (plasma PLP 20-30 nmol/L) on the rate of red blood cell (RBC) glutathione synthesis. DESIGN: We measured plasma and RBC glutathione concentrations and the fractional and absolute synthesis rates of RBC glutathione using the stable-isotope-labeled glutathione precursor [1,2-(13)C(2)]glycine in 13 healthy volunteers aged 21-39 y. RESULTS: Dietary vitamin B-6 restriction did not significantly affect the glutathione concentration in plasma (6.9 +/- 1.9 compared with 6.7 +/- 1.1 micromol/L) or RBCs (2068 +/- 50 compared with 2117 +/- 48 micromol/L). For RBC glutathione, the mean fractional synthesis rates were 54 +/- 5%/d and 43 +/- 4%/d (P = 0.10), and the absolute synthesis rates were 1116 +/- 100 and 916 +/- 92 micromol . L(-1) . d(-1) (P = 0.14) before and after vitamin B-6 restriction, respectively. CONCLUSIONS: Marginal vitamin B-6 deficiency tended to decrease mean RBC glutathione synthesis with no effect on RBC glutathione concentration, but the responses varied widely among individuals. Because the cysteine concentration in plasma and RBC did not change during vitamin B-6 restriction, we conclude that the effects of marginal vitamin B-6 deficiency on glutathione synthesis are not caused by altered precursor concentrations.

New treatment paradigms in neonatal metabolic epilepsies.

Neonatal seizures represent a major challenge among the epilepsies vis-à-vis seizure classification, electroclinical correlation, inherent excitability of neocortex, ontogenic characteristics of neurotransmitter receptors, and responsiveness to standard antiepileptic drugs. Each of these factors renders neonatal seizures more difficult to treat, and therapy has been a vexing area for recent advances in this seizure category. Conversely, specific metabolic disorders have very special therapeutic considerations in the clinical setting of neonatal seizures which require a high index of clinical suspicion and rapid intervention for a successful outcome. The prototype is pyridoxine dependency, although pyridoxal 5'-phosphate dependency is a recently recognized but treatable neonatal epilepsy that deserves earmarked distinction. Clinicians must remain vigilant for these possibilities, including atypical cases where apparent seizure-free intervals may occur. Folinic acid-dependent seizures are allelic with pyridoxine dependency. Serine-dependent seizures and glucose transporter deficiency may present with neonatal seizures and have specific therapy. A vital potassium channel regulated by serum ATP/ADP ratios in the pancreas and brain may be mutated with a resultant neuroendocrinopathy characterized by development delay, epilepsy, and neonatal diabetes (DEND). This requires oral hypoglycaemic therapy, and not insulin, for neurological responsiveness. The startle syndrome of hyperekplexia, which mimics neonatal epilepsy, has been associated with laryngospasm and sudden death but is treated with benzodiazepines.

Vitamin B6 status, deficiency and its consequences - an overview / Estado de vitamina B6, deficiencia y sus consecuencias — una revisión

Background: Vitamin B6 is thought to be a most versatile coenzyme that participates in more than 100 biochemical reactions. It is involved in amino acid and homocysteine metabolism, glucose and lipid metabolism, neurotransmitter production and DNA/RNA synthesis. Vitamin B6 can also be a modulator of gene expression. Nowadays, clinically evident vitamin B6 deficiency is not a common disorder, at least in the general population. Nevertheless, a subclinical, undiagnosed deficiency may be present in some subjects, particularly in the elderly.Objective: This review gives a complete overview over the metabolism and interactions of vitamin B6. Further, we show which complications and deficiency symptoms can occur due to a lack of vitamin B6 and possibilities for public health and supplemental interventions. Methods: The database Medline (www.ncvi.nlm.nih.gov) was searched for terms like "vitamin B6", "pyridoxal", "cancer", "homocysteine", etc. For a complete understanding, we included studies with early findings from the forties as well as recent results from 2006. These studies were summarised and compared in different chapters. Result and conclusion: In fact, it has been proposed that suboptimal vitamin B6 status is associated with certain diseases that particularly afflict the elderly population: impaired cognitive function, Alzheimer's disease, cardiovascular disease, and different types of cancer. Some of these problems may be related to the elevated homocysteine concentrations associated to vitamin B6 deficiency, but there is also evidence for other mechanisms independent of homocysteine by which a suboptimal vitamin B6 status could increase the risk for these chronic diseases (AU)

Antecedentes: se piensa que la vitamina B6 es la coenzima más versátil que participa en más de 100 reacciones bioquímicas. Está implicada en el metabolismo de los aminoácidos y de la homocisteína, el metabolismo de la glucosa y los lípidos, en la producción de neurotransmisores y en la síntesis de ADN/ARN. Esta vitamina también puede ser un modulador de la expresión génica. Hoy en día, la deficiencia clínicamente evidente de vitamina B6 no es una afección habitual, al menos en la población general. Sin embargo, puede ocurrir una deficiencia subclínica no diagnosticada en algunos individuos, especialmente en los ancianos. Objetivo: esta revisión aporta una visión de conjunto completa sobre el metabolismo y las interacciones de la vitamina B6. Además, mostramos qué complicaciones y síntomas por deficiencia pueden ocurrir por la falta de vitamina B6 y las posibilidades de intervenciones de salud pública y de suplementos. Métodos: se buscó en la base de datos Medline (www.ncvi.nlm.nih.gov) con los términos "vitamin B6", "pyridoxal", "cancer", "homocysteine", etc. Para una mayor comprensión, incluimos estudios con hallazgos iniciales de los años cuarenta, así como estudios recientes del año 2006. Se resumieron estos estudios y se compararon por capítulos diferentes. Resultados y Conclusión: de hecho, se ha propuesto que el estado sub-óptimo de vitamina B6 se asocia con ciertas enfermedades que afligen en especial a la población anciana: función cognitiva alterada, enfermedad de Alzheimer, cardiopatía y distintos tipos de cáncer. Algunos de estos problemas podrían relacionarse con concentraciones elevadas de homocisteína asociadas con una deficiencia de vitamina B6, pero también existe la evidencia de otros mecanismos independientes de la homocisteína por los que un estado sub-óptimo de vitamina B6 podría aumentar el riesgo de padecer estas enfermedades crónicas (AU)

Vitamin B6 status, deficiency and its consequences--an overview.

BACKGROUND: Vitamin B6 is thought to be a most versatile coenzyme that participates in more than 100 biochemical reactions. It is involved in amino acid and homocysteine metabolism, glucose and lipid metabolism, neurotransmitter production and DNA/RNA synthesis. Vitamin B6 can also be a modulator of gene expression. Nowadays, clinically evident vitamin B6 deficiency is not a common disorder, at least in the general population. Nevertheless, a subclinical, undiagnosed deficiency may be present in some subjects, particularly in the elderly. OBJECTIVE: This review gives a complete overview over the metabolism and interactions of vitamin B6. Further, we show which complications and deficiency symptoms can occur due to a lack of vitamin B6 and possibilities for public health and supplemental interventions. METHODS: The database Medline (www.ncvi.nlm.nih.gov) was searched for terms like "vitamin B6", "pyridoxal", "cancer", "homocysteine", etc. For a complete understanding, we included studies with early findings from the forties as well as recent results from 2006. These studies were summarised and compared in different chapters. RESULTS AND CONCLUSION: In fact, it has been proposed that suboptimal vitamin B6 status is associated with certain diseases that particularly afflict the elderly population: impaired cognitive function, Alzheimer's disease, cardiovascular disease, and different types of cancer. Some of these problems may be related to the elevated homocysteine concentrations associated to vitamin B6 deficiency, but there is also evidence for other mechanisms independent of homocysteine by which a suboptimal vitamin B6 status could increase the risk for these chronic diseases.

Vitamin deficiency and hyperhomocysteinemia in pseudoexfoliation glaucoma.

Pseudoexfoliation syndrome (PEX) is a systemic disorder characterized by the deposition of an abnormal fibrillar material in ocular and various extraocular tissues. It represents the most common identifiable cause of glaucoma (PEX glaucoma = PEXG). Due to similar pathogenetic mechanisms, glaucoma has been called "ocular Alzheimer's disease". PEXG and Alzheimer's disease share common associations such as the higher prevalence of hyperhomocysteinemia in both disorders. In order to investigate the cause of hyperhomocysteinemia in PEXG, we evaluated B-vitamin levels (folate, B12, B6) and their associations with homocysteine (Hcy) in plasma of 70 PEXG patients and 70 control subjects. Folate, vitamin B12 and B6 levels were significantly decreased and associated with elevated Hcy levels in PEXG. Low B-vitamin levels in PEX might also help explain, at least in part, the higher prevalence of B-vitamin deficiency in disorders associated with PEX such as Alzhemier's disease.

Inflammation causes tissue-specific depletion of vitamin B6.

Previously we observed strong and consistent associations between vitamin B6 status and several indicators of inflammation in patients with rheumatoid arthritis. Clinical indicators, including the disability score, the length of morning stiffness, and the degree of pain, and biochemical markers, including the erythrocyte sedimentation rate and C-reactive protein levels, were found to be inversely correlated with circulating vitamin B6 levels. Such strong associations imply that impaired vitamin B6 status in these patients results from inflammation. In the present study we examined whether inflammation directly alters vitamin B6 tissue contents and its excretion in vivo. A cross-sectional case-controlled human clinical trial was performed in parallel with experiments in an animal model of inflammation. Plasma and erythrocyte and pyridoxal 5'-phosphate concentrations, urinary 4-pyridoxic acid excretion, and the activity coefficient of erythrocyte aspartate aminotransferase were compared between patients and healthy subjects. Adjuvant arthritis was induced in rats for investigating hepatic and muscle contents as well as the urinary excretion of vitamin B6 during acute and chronic inflammation. Patients with rheumatoid arthritis had low plasma pyridoxal 5'-phosphate compared with healthy control subjects, but normal erythrocyte pyridoxal 5'-phosphate and urinary 4-pyridoxic acid excretion. Adjuvant arthritis in rats did not affect 4-pyridoxic acid excretion or muscle storage of pyridoxal 5'-phosphate, but it resulted in significantly lower pyridoxal 5'-phosphate levels in circulation and in liver during inflammation. Inflammation induced a tissue-specific depletion of vitamin B6. The low plasma pyridoxal 5'-phosphate levels seen in inflammation are unlikely to be due to insufficient intake or excessive vitamin B6 excretion. Possible causes of decreased levels of vitamin B6 are discussed.

Vitamin B-6 deficiency prolongs the time course of evoked dopamine release from rat striatum.

Vitamin B-6-deficient animals exhibit motor abnormalities. To investigate the possible physiologic alterations in the dopaminergic nervous system in vitamin B-6 deficiency, dopamine release in the striatum of vitamin B-6-deficient rats was determined using in vivo electrochemistry. Male Sprague-Dawley rats, 3 wk old, weighing 50-60 g, were randomly assigned to a control (7 mg pyridoxine HCl/kg diet), vitamin B-6-deficient (0 mg pyridoxine HCl/kg diet), or pair-fed (7 mg pyridoxine HCl/kg diet) group. After 8 wk of dietary treatment, plasma concentrations of pyridoxal 5'-phosphate as well as the striatal pyridoxal 5'-phosphate and pyridoxamine 5'-phosphate were significantly lower in the vitamin B-6-deficient group than in the control and pair-fed groups. The dopamine concentrations of the striatum and the magnitude of the dopamine release after local application of KCl did not differ among the groups. However, the time required for KCl-evoked dopamine release to reach its peak level was significantly longer for the vitamin B-6-deficient rats than for controls. In addition, the decay time from the peak to one-half of the KCl-evoked dopamine release was also significantly prolonged in vitamin B-6-deficient rats compared with the control group. The results indicate that the cellular content of dopamine does not reflect the functional state of dopaminergic neurons in vitamin B-6 deficiency. The time course for release of dopamine and decay of the released dopamine is prolonged by vitamin B-6 deficiency, which might contribute to the motor abnormalities of the deficient rats.

Pharmacorefractory status epilepticus due to low vitamin B6 levels during pregnancy.

We report a patient with pyridoxine-dependent epileptic seizures during early childhood. She had been completely seizure free for 23 years until she became pregnant. During the week 14 of her pregnancy, status epilepticus developed and was refractory to antiepileptic drugs but responded to intravenous administration of vitamin B6. Vitamin B6 levels were found to be decreased during pregnancy, although the patient reported continued and regular oral supplementation. Possible reasons for decreased vitamin B6 levels leading to status epilepticus are discussed.