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PubMed2006

Contrasting behaviors of mutant cystathionine beta-synthase enzymes associated with pyridoxine response.

Cystathionine beta-synthase (CBS) deficiency is a recessive genetic disorder characterized by extremely elevated levels in plasma homocysteine. Patients homozygous for the I278T or R266K mutations respond clinically to pharmacologic doses of pyridoxine, the precursor of a cofactor for the enzyme, 5'-pyridoxal phosphate (PLP). Here we test the hypothesis that these mutations are pyridoxine responsive because they lower the affinity of the enzyme for PLP. We show that recombinant R266K has 30 to 100% of the specific activity of the wild-type enzyme, while I278T only has only 1 to 5% activity. Kinetic studies show that the decreased activity in both enzymes is due to reduced turnover rate and not substrate binding. Neither I278T nor R266K appear to greatly affect multimer status of the enzyme. The R266K enzyme has reduced affinity for PLP compared to the wild-type enzyme, providing a mechanism for the pyridoxine response observed in patients. Surprisingly, the I278T enzyme does not have altered affinity for PLP. To confirm that this was not an in vitro artifact, we examined pyridoxine response in mice that stably express human I278T as their sole source of CBS activity. These mice have extremely elevated plasma homocysteine levels and do not respond significantly to large doses of pyridoxine. Our findings suggest that there may be multiple mechanisms involved in response to pyridoxine.

Alleles↗
PubMed2007

Biochemical and molecular characterization of 18 patients with pyridoxine-dependent epilepsy and mutations of the antiquitin (ALDH7A1) gene.

Patients with pyridoxine dependent epilepsy (PDE) present with early-onset seizures resistant to common anticonvulsants. According to the benefit of pyridoxine (vitamin B(6)) and recurrence of seizures on pyridoxine withdrawal, patients so far have been classified as having definite, probable, or possible PDE. Recently, PDE has been shown to be caused by a defect of alpha-amino adipic semialdehyde (AASA) dehydrogenase (antiquitin) in the cerebral lysine degradation pathway. The accumulating compound piperideine-6-carboxylic acid (P6C) was shown to inactivate pyridoxalphosphate (PLP) by a Knoevenagel condensation. Pipecolic acid (PA) and AASA are markedly elevated in urine, plasma, and cerebrospinal fluid (CSF) and thus can be used as biomarkers of the disease. We have investigated 18 patients with neonatal seizure onset, who have been classified as having definite (11), probable (four), or possible (three) PDE. All patients had elevated PA and AASA in plasma (and urine) while on treatment with individual dosages of pyridoxine. Within this cohort, molecular analysis identified 10 novel mutations (six missense mutations, one nonsense mutation, two splice site mutations) within highly conserved regions of the antiquitin gene. Seven mutations were located in exonic sequences and two in introns 7 and 17. Furthermore, a novel deletion of exon 7 was identified. Two of the 36 alleles investigated require further investigation. A known mutation (p.Glu399Gln) was found with marked prevalence, accounting for 12 out of 36 alleles (33%) within our cohort. Pyridoxine withdrawal is no longer needed to establish the diagnosis of "definite" PDE. Administration of pyridoxine in PDE may not only correct secondary PLP deficiency, but may also lead to a reduction of AASA (and P6C) as presumably toxic compounds.

Aldehyde Dehydrogenase↗
PubMed1994

Effects of serotonergic agents on plasma prolactin levels in pyridoxine-deficient adult male rats.

Plasma concentration of prolactin was significantly reduced in pyridoxine-deficient as compared to control (pyridoxine-supplemented) adult male rats. Administration of pyridoxine to deficient rats resulted in a significant increase in plasma prolactin. The reduction in plasma prolactin in pyridoxine-deficient rats corresponded with the significantly reduced hypothalamic contents of pyridoxal phosphate and serotonin in pyridoxine-deficient rats. Plasma prolactin concentrations were also measured in response to serotonergic agents in both groups of rats. The administration of the 5HT1A agonist (8-hydroxy 2-n-dipropylamino tetralin) resulted in a significant increase in plasma prolactin and that of the specific 5HT1A antagonist spiroxatrine had the opposite effect. The results suggest that the hypothalamic serotonergic regulation of prolactin release is impaired in pyridoxine deficiency.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1985

Recent advances in the mechanism of pyridoxine-responsive disorders.

Pyridoxine metabolism is summarised and speculation on possible defects leading to disease is made. Inherited deficiencies of PLP enzymes, which are known to respond in vivo to pharmacologic doses of pyridoxine are listed. The mechanism of pyridoxine responsiveness in homocystinuria due to cystathionine beta-synthase deficiency is discussed. There is a correlation in most (but not all) cases between the presence of residual CS activity, which is often stimulated by pyridoxal phosphate much more than control enzyme, in cultured fibroblasts and pyridoxine responsiveness in vivo. Exceptional patients have been found and are discussed in the light of more detailed studies on their cell lines. Clearly defined abnormalities of pyridoxal phosphate binding to mutant enzyme have been demonstrated and evidence of reduced intracellular stability of mutant CS and possible modulation by pyridoxal phosphate is presented. Preliminary findings suggest that the tissue level of pyridoxal phosphate achieved following pyridoxine treatment could be one other factor in determining pyridoxine responsiveness.

Cells, Cultured↗
PubMed1992

Effect of pyridoxine on tumor necrosis factor activities in vitro.

Clinical trials with tumor necrosis factor (TNF) as an antitumor agent have so far given rather disappointing results. In this study we show that the naturally occurring vitamin B6 compound, pyridoxine, enhances TNF-induced cytolysis of three subclones of a mouse fibrosarcoma cell line (WEHI 164). The degree of pyridoxine-induced enhancement of TNF cytotoxicity seems to be dependent on the cells sensitivity to TNF, as the enhancement was much more pronounced in the relatively TNF resistant subclone act-R(cl.12)-WEHI 164, than in the very TNF sensitive subclone WEHI 164 clone 13. Furthermore, our study shows that pyridoxine, in contrast to its enhancing effect on TNF-induced cytotoxicity, rather inhibits TNF-induced growth of human FS-4 fibroblasts. Pyridoxine also enhances lymphotoxin (LT)-induced tumor cell killing and inhibits LT-induced fibroblast growth. Pyridoxine is a relatively non-toxic agent in vivo. Our results suggest that a combination of TNF and pyridoxine may be more efficient than TNF alone, in the treatment of cancer patients.

Animals↗
PubMed1988

Dietary pyridoxine interaction with tryptophan or histidine on brain serotonin and histamine metabolism.

We studied the metabolic effects of high dietary intakes of pyridoxine and of the substrate-cofactor interaction between dietary histidine or tryptophan and pyridoxine in rat brain. In the substrate-cofactor interaction study, histamine and serotonin levels were determined in rats fed elevated or requirement levels of substrate (histidine: 0.3% and 0.8%, tryptophan: 0.15% and 0.6%) and excess or requirement levels of pyridoxine HCl (7 mg vs. 3,000 mg/kg). Excess pyridoxine intake caused a differential effect on brain histamine concentration--inhibitory with the requirement level of histidine (-29%), and stimulatory (+21%) with the elevated level of histidine. When dietary tryptophan was fed at the requirement level, excess pyridoxine caused essentially no changes in hypothalamic serotonin and 5HIAA (-2%, -2%). With elevated tryptophan intake, excess pyridoxine significantly increased serotonin and 5HIAA (+32%, +20%) in the hypothalamus. These results indicate a clear interaction between substrate and coenzyme precursor which influences brain metabolism of histamine and serotonin.

Animals↗
PubMed1992

Formation of beta-galactosyl compounds of pyridoxine in growing culture of Sporobolomyces singularis.

Several pyridoxine compounds were found to be formed in a high yield in a growing culture of Sporobolomyces singularis containing lactose and pyridoxine. Three compounds, I, II and III, were isolated from cultured broth by Dowex 50W-X8 column chromatography, paper chromatography, lyophilization, and then obtained as needle crystals (m.p. (decomp.): I, 204-206 degrees C; II, 192-194 degrees C; III, 222-223 degrees C. [alpha]D16: I, -27.7 degrees (c = 3.82, H2O); II, -1.6 degrees (c = 2.52, H2O); III, +8.3 degrees (c = 3.98, H2O)). Compounds I, II and III were identified as 5'-O-(beta-D-galactopyranosyl)-pyridoxine, 4'-O-(beta-D-galactopyranosyl)-pyridoxine, and 4'-O-(beta-D-galactopyranosyl-(1----4)-beta-D-galactopyranosyl)-pyrid oxi ne, respectively, on the basis of the various experimental results, viz., ultraviolet, infra-red, 1H-NMR, and 13C-NMR spectra, products by hydrolysis with acid and with alpha- and beta-galactosidases, migration on paper electrophoresis, and Gibbs reaction in the presence and absence of boric acid. Also, the yeast produced a remarkable amount of beta-glucosyl compounds of pyridoxine in cultured broth, when grown on cellobiose and pyridoxine.

Carbohydrate Sequence↗
PubMed1995

Origin of the nitrogen atom of pyridoxine in Saccharomyces cerevisiae.

The origin of the nitrogen atom of pyridoxine was studied in Saccharomyces cerevisiae. The 15N atom of 15NH4Cl added to the growth medium as the nitrogen source was incorporated efficiently into the nitrogen atom of pyridoxine. The competitive effects of 14N-amino acids on the incorporation of 15NH4Cl were examined. Incorporation of 15N into pyridoxine was inhibited by glutamine. The label of L-[amide-15N]glutamine was incorporated effectively into pyridoxine in S. cerevisiae. On the other hand, the label from L-[amide-15N]glutamine was not incorporated into pyridoxine in Escherichia coli. These findings suggest that the biosynthetic pathway of pyridoxine in S. cerevisiae differs from that in E. coli.

Escherichia coli↗
PubMed1992

Lack of hormonal stimulation of pyridoxine metabolism in isolated rat hepatocytes.

Isolated hepatocytes obtained from Sprague-Dawley rats (145-175 g) were incubated for 15 min at 30 degrees C in Krebs-Henseleit bicarbonate buffer, pH 7.4, containing 0.5 mM concentration of each of the 20 natural amino acids and either 4.5 or 23 microM [U-14C]pyridoxine. Pyridoxine, pyridoxal, pyridoxal phosphate, and pyridoxic acid separated by an anion-exchange chromatographic technique were quantified using a phosphate analyzer and a liquid scintillation counter. The conversion of [U-14C]pyridoxine to its metabolites was more than doubled by increasing the amount of pyridoxine (4.5 to 23 microM) in the incubation medium. Insulin (10 mU/ml), glucagon (1 nM), or epinephrine (10 microM) did not have any significant effect on the conversion of [14C]-pyridoxine to pyridoxal, pyridoxal phosphate, or pyridoxic acid. Our earlier observations of a large decrease in serum pyridoxal phosphate in the diabetic rat cannot be explained by any direct hormonal effects on pyridoxine metabolism.

Animals↗
PubMed2004

Pyridoxine-induced toxicity in rats: a stereological quantification of the sensory neuropathy.

Excess ingestion of pyridoxine (vitamin B6) causes a severe sensory neuropathy in humans. The mechanism of action has not been fully elucidated, and studies of pyridoxine neuropathy in experimental animals have yielded disparate results. Pyridoxine intoxication appears to produce a neuropathy characterized by necrosis of dorsal root ganglion (DRG) sensory neurons and degeneration of peripheral and central sensory projections, with large diameter neurons being particularly affected. The major determinants affecting the severity of the pyridoxine neuropathy appear to be duration and dose of pyridoxine administration, differential neuronal vulnerability, and species susceptibility. The present study used design-based stereological techniques in conjunction with electrophysiological measures to quantify the morphological and physiological changes that occur in the DRG and the distal myelinated axons of the sciatic nerve following pyridoxine intoxication. This combined stereological and electrophysiological method demonstrates a general approach that could be used for assessing the correlation between pathophysiological and functional parameters in animal models of toxic neuropathy.

Animals↗
PubMed1996

The uptake of Mn-DPDP by hepatocytes is not mediated by the facilitated transport of pyridoxine.

Manganese-dipyridoxal diphosphate (Mn-DPDP) is a liver-selective contrast agent selectively taken up by the hepatocytes. Because of the analogy of structure with pyridoxine (vitamin B6), it was previously suggested that this compound can be selectively taken up by the facilitated transport of vitamers B6. To understand the uptake mechanism, an in vivo binding study was performed based on a competition between 54Mn-DPDP and pyridoxine on the one hand, and Mn-DPDP and [3H]pyridoxine on the other. We found that the [3H]pyridoxine levels in the liver were not significantly different 5 min after intravenous administration of several doses of Mn-DPDP (5 nmol/kg to 50 mumol/kg): 5.0 +/- 0.3% of the injected dose/g tissue. The content of 54Mn (administered as 54Mn-DPDP) in the liver was not affected by a saturation dose of pyridoxine (1 mmol/kg) and was found to be constant (+/- 10% of the injected dose/g tissue) for 60 min. These experiments showed that the uptake of Mn-DPDP is not mediated by the transporter of pyridoxine.

Animals↗
PubMed1992

Disturbance of GABA metabolism in pyridoxine-dependent seizures.

In an infant with typical pyridoxine-dependent seizures, CSF GABA level, was determined before treatment with pyridoxine. Before onset of treatment, level of GABA in CSF was highly lowered (16 pmol/ml), pyridoxine level in serum was within normal range. Immediately after application of 80 mg pyridoxine fits stopped and the EEG was without seizure activity. The data substantiate previous findings in brain tissue from a patient with pyridoxine-dependent seizures. They are proof of a disturbed GABA metabolism in pyridoxine dependent seizures.

Brain↗
PubMed2001

Intravenous pyridoxine-induced metabolic acidosis.

STUDY OBJECTIVE: Pyridoxine hydrochloride, the antidote for isonicotinic acid hydrazide (INH)--induced seizures, is available in solution at a concentration of 100 mg/mL at a pH of less than 3. Pyridoxine is often infused rapidly in large doses for INH-induced seizures. Effects of pyridoxine infusion on base deficit in amounts given for INH poisoning have not been studied in human subjects. We hypothesized that this infusion would result in transient worsening of acidosis. METHODS: We conducted a randomized, controlled crossover trial in human volunteers. Five healthy volunteers (mean age, 35 years; range, 29 to 43 years) were randomized to receive intravenous placebo (50 mL of normal saline solution) or 5 g of pyridoxine (50 mL) over 5 minutes. A peripheral intravenous catheter was established in each arm, and a heparinized venous blood sample was obtained for base deficit at baseline and 3, 6, 10, 20, and 30 minutes after infusion. After at least a 1-week washout period, the volunteers were assigned to the alternate arms of the experiments, thus acting as their own control subjects. Data were analyzed by using the 2-tailed paired t test, controlling for multiple comparisons. RESULTS: No difference was noted between groups at baseline. A statistically significant increased base deficit was noted after the pyridoxine infusion versus control at 3 to 20 minutes but not at 30 minutes (P =.1). Maximal mean increase in base deficit (2.74 mEq/L) was noted at 3 minutes. CONCLUSION: A transient increase in base deficit occurs after the infusion of 5 g of pyridoxine in normal volunteers.

Acidosis↗
PubMed1993

Defective 3,4-dihydroxyphenylalanine decarboxylation to dopamine in hydralazine-treated hypertensive patients may be pyridoxine remediable.

The previously observed defective dopamine (DA) generation from 3,4-dihydroxyphenylalanine (DOPA) can also be seen in patients treated for many years by hydralazine. This may be due to a hydralazine-induced depletion of pyridoxine, an essential coenzyme of the aromatic L-amino acid decarboxylase (LAAD). Eleven hydralazine-treated stable essential hypertensive (EH) patients, initially found to have a defect in the DOPA decarboxylation to DA, tested by a single DOPA administration (500 mg, orally), were retested by the same test 4 days after pyridoxine pretreatment (100 mg/day) for data on blood pressure (BP), pulse rate, and renal and plasma catecholamines and their metabolites, as well as plasma atrial natriuretic factor (ANF), cyclic GMP (cGMP), plasma renin activity (PRA), and plasma aldosterone (PA). Initially, hydralazine-treated stable EH patients manifested, following DOPA administration, lower DOPA decarboxylation to DA than control subjects. Pyridoxine pretreatment accelerated DA generation from exogenous DOPA and attenuated the DOPA-induced increases in plasma and urinary DOPA and its metabolite 3-O-methyl-DOPA, but accentuated the increase in free DA and its main metabolites, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), while BP, ANF, cGMP, PRA, and PA remained unaffected. The DOPA-induced increments of urinary DA were, in contrast to plasma DA changes, blunted by pyridoxine pretreatment. The attenuation of the sodium excretion by pyridoxine pretreatment exceeded that of the DA excretion, suggesting that pyridoxine suppressed a natriuretic factor, other than ANF, or activated a sodium-retaining factor, other than renin or aldosterone.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1977

Uptake of pyridoxine hydrochloride by the rat jejunal mucosa in vitro.

The kinetics of mucosal membrane transport of pyridoxine hydrochloride were evaluated in vitro in the rat jejunum. Utilizing everted sacs and a double-label isotope technique, short-term incubation within the period of initial linear tissue uptake indicated: 1) no evidence of saturation of uptake over a wide pyridoxine-HCl concentration range (0.01 muM-10 mM); 2) failure of 4-deoxypyridoxine (10 muM), anoxia, iodoacetamide (5 mM), Na+ replacement and ouabain (1 mM) to inhibit uptake of 2 muM pyridoxine-HCl significantly; and 3) a low Q10 value of 1.31. Using single-label techniques, sacs were also incubated for 1 hour in 2 muM pyridoxine HCl with determination of the apparent tissue water-mucosal fluid concentration ratio and chromatographic separation of the various forms of vitamin B6 in tissue. Results demonstrated a failure of pyridoxine in tissue water to achieve a concentration in excess of that in the incubation medium. Data, therefore, were most consistent with passive diffusion as the mechanism for in vitro jejunal mucosal uptake of pyridoxine-HCl in the rat.

Animals↗
PubMed1979

Pyridoxine requirements of channel catfish.

In 20 and 12 week feeding trials, channel catfish fingerlings were fed purified diets containing five levels (0, 5, 10, 20, and 30 mg/kg) and six levels (0, 1, 2, 5, 10, and 20 mg/kg) of supplemental pyridoxine hydrochloride. Fish fed unsupplemented diets (pyridoxine content of 1.2 mg/kg) were characterized by anoxeria, nervous disorders, tetany, greenish-blue body coloration, and eventual mortality. Anemia, which has been reported in pyridoxine deficient salmonids, was not observed in pyridoxine deficient catfish. However, a microcytic, normochromic anemia was observed in groups fed high dietary levels of pyridoxine (20 mg/kg or greater). The dietary pyridoxine level required for maximal growth was approximately 3 mg/kg of diet. All other deficiency signs were prevented by 2.2 mg/kg of diet.

Animals↗
PubMed1979

Influence of dietary pyridoxine on selected immune capacities of rat dams and pups.

The influence of dietary pyridoxine on passive antibody transfer from dams to pups and on active humoral antibody formation by the pups was studied. Rats were fed diets containing 20.0, 0.6, 0.45, or 0.3 mg pyridoxine-HCl/kg during gestation and 20.0, 0.4, 0.3, or 0.2 mg/kg during lactation (diets A, B, C, and D). Diets B, C, and D contained 100, 75, and 50% of the NRC requirement for pyridoxine during gestation and lactation. After pups in groups B, C, and D developed signs of pyridoxine deficiency, all dams were fed diet A on days 9 to 21 of lactation. On day 9 vitamin B-6 levels were lower in spleens and thymuses of pups and in milk in groups B, C, and D. However, IgG in sera of dams and pups and in milk indicated that passive antibody transfer was similar for all groups. After weaning, pups in groups A, B, C, and D were fed diets containing 20.0, 0.4, 0.2, and 0 mg vitamin B-6/kg, respectively. On day 35 vitamin B-6 levels were lower in spleens and thymuses of pups fed inadequate pyridoxine (groups B, C, and D). These pups had fewer spleen cells and splenic antibody-forming cells (AFC) and lower levels of humoral antibody. The reduction in spleen cells and splenic AFC resulted in part from lower food intake but was intensified by pyridoxine deprivation.

Aging↗
PubMedDate not supplied

Plasma pyridoxine deficiency is related to increased psychological distress in recently bereaved homosexual men.

OBJECTIVE: Previous research has demonstrated that a theoretical model including measures of life stressors, social support, and coping style significantly predicts psychological distress. This study tested plasma pyridoxine (vitamin B6) deficiency status as a predictor of overall psychological distress and specific mood states in this model, controlling for HIV-1 serostatus. METHOD: Subjects included HIV-1+ (N = 76) and HIV-1- (N = 58) recently bereaved homosexual men. At baseline, subjects completed a battery of psychosocial questionnaires, together with a physical examination and venipuncture. The Profile of Mood States (POMS) provided measures of overall psychological distress as well as specific mood states. Pyridoxine deficiency status (a categorical measure of deficient vs. adequate status) was determined with a bioassay of erythrocyte aspartate aminotransferase activity. RESULTS: Pyridoxine deficiency was a significant predictor of increased overall psychological distress in this model, controlling for life stressors, social support, coping style, and HIV-1 serostatus. In post hoc analyses of specific mood state effects, pyridoxine deficiency status was significantly associated with increases in depressed, fatigued, and confused mood levels, but not with those of anxiety, anger, or vigor. DISCUSSION: These findings suggest that adequate pyridoxine status may be necessary to avert psychological distress in the setting of bereavement. Inasmuch as pyridoxine is a cofactor for 5-hydroxytryptophan decarboxylase--an enzyme in the biosynthesis pathway of serotonin--serotonin level in the brain is implicated as the mediating factor.

Adaptation, Psychological↗