Research Notes: Pyridoxine (Vitamin B-6)

Chem Biol Interact. 2006 Oct 27.
Mitochondrial function and toxicity: role of B vitamins on the one-carbon transfer pathways.
Depeint F, Bruce WR, Shangari N, Mehta R, O'Brien PJ.
Department of Pharmaceutical Sciences, University of Toronto, Canada; Department of Nutritional Sciences, University of Toronto, Canada.

The B vitamins are water-soluble vitamins that are required as coenzymes for reactions essential for cellular function. This review focuses on the essential role of vitamins in maintaining the one-carbon transfer cycles. Folate and choline are believed to be central methyl donors required for mitochondrial protein and nucleic acid synthesis through their active forms, 5-methyltetrahydrofolate and betaine, respectively. Cobalamin (B12) may assist methyltetrahydrofolate in the synthesis of methionine, a cysteine source for glutathione biosynthesis. Pyridoxal, pyridoxine and pyridoxamine (B6) seem to be involved in the regeneration of tetrahydrofolate into the active methyl-bearing form and in glutathione biosynthesis from homocysteine. Other roles of these vitamins that are relevant to mitochondrial functions will also be discussed. However these roles for B vitamins in cell function are mostly theoretically based and still require verification at the cellular level. For instance it is still not known what B vitamins are depleted by xenobiotic toxins or which cellular targets, metabolic pathways or molecular toxic mechanisms are prevented by B vitamins. This review covers the current state of knowledge and suggests where this research field is heading so as to better understand the role vitamin Bs play in cellular function and intermediary metabolism as well as molecular, cellular and clinical consequences of vitamin deficiency. The current experimental and clinical evidence that supplementation alleviates deficiency symptoms as well as the effectiveness of vitamins as antioxidants will also be reviewed.

J Inherit Metab Dis. 2006 Apr.
B(6)-responsive disorders: A model of vitamin dependency.
Clayton PT.
Biochemistry, Endocrinology and Metabolism, Institute of Child Health, 30 Guilford St, London, UK.

Pyridoxal phosphate is the cofactor for over 100 enzyme-catalysed reactions in the body, including many involved in the synthesis or catabolism of neurotransmitters. Inadequate levels of pyridoxal phosphate in the brain cause neurological dysfunction, particularly epilepsy. There are several different mechanisms that lead to an increased requirement for pyridoxine and/or pyridoxal phosphate. These include: (i) inborn errors affecting the pathways of B(6) vitamer metabolism; (ii) inborn errors that lead to accumulation of small molecules that react with pyridoxal phosphate and inactivate it; (iii) drugs that react with pyridoxal phosphate; (iv) coeliac disease, which is thought to lead to malabsorption of B(6) vitamers; (v) renal dialysis, which leads to increased losses of B(6) vitamers from the circulation; (vi) drugs that affect the metabolism of B(6) vitamers; and (vii) inborn errors affecting specific pyridoxal phosphate-dependent enzymes. The last show a very variable degree of pyridoxine responsiveness, from 90% in X-linked sideroblastic anaemia (delta-aminolevulinate synthase deficiency) through 50% in homocystinuria (cystathionine beta-synthase deficiency) to 5% in ornithinaemia with gyrate atrophy (ornithine delta-aminotransferase deficiency). The possible role of pyridoxal phosphate as a chaperone during folding of nascent enzymes is discussed. High-dose pyridoxine or pyridoxal phosphate may have deleterious side-effects (particularly peripheral neuropathy with pyridoxine) and this must be considered in treatment regimes. None the less, in some patients, particularly infants with intractable epilepsy, treatment with pyridoxine or pyridoxal phosphate can be life-saving, and in other infants with inborn errors of metabolism B(6) treatment can be extremely beneficial.

J Altern Complement Med. 2006 Jan-Feb.
Abnormally high plasma levels of vitamin B6 in children with autism not taking supplements compared to controls not taking supplements.
Adams JB, George F, Audhya T.
Arizona State University, Tempe, AZ, USA.

Background: There have been many studies of the effect of high-dose supplementation of vitamin B6 on children and adults with autism, with all but one reporting benefits. Objective: The aim of this study was to investigate the biochemical basis for vitamin B6 therapy by measuring the level of total vitamin B6 in the plasma of unsupplemented children with autism spectrum disorder compared to unsupplemented control subjects. Participants: Children with autism spectrum disorders (n = 35, age 3-9 years) and unrelated typical children (n = 11, age 6-9 years), all from Arizona, were studied. (This includes the data from 24 children with autism from our previous study.) Methodology: A microbiologic assay was used to measure the level of total vitamin B6 (including phosphorylated and unphosphorylated forms), in a blinded fashion. Results: Children with autism had a 75% higher level of total vitamin B6 than the controls (medians of 56 versus 32 ng/mL, respectively, p = 0.00002). Most of the autistic children (77%) had levels that were more than 2 standard deviations above the median value of the controls. The autistic girls (n = 5) also had elevated levels (mean of 54.6 ng/mL, median of 60 ng/mL). Discussion: These results are consistent with previous studies that found that: (1) pyridoxal kinase had a very low activity in children with autism and (2) pyridoxal 5 phosphate (PLP) levels are unusually low in children with autism. Thus, it appears that the low conversion of pyridoxal and pyridoxine to PLP results in low levels of PLP, which is the active cofactor for 113 known enzymatic reactions, including the formation of many key neurotransmitters. Conclusions: Total vitamin B6 is abnormally high in autism, consistent with previous reports of an impaired pyridoxal kinase for the conversion of pyridoxine and pyridoxal to PLP. This may explain the many published studies of benefits of high-dose vitamin B6 supplementation in some children and adults with autism.

Cochrane Database Syst Rev. 2003.
The effect of vitamin B6 on cognition.
Malouf R, Grimley Evans J.
Dept. of Clinical Geratology, Cochrane Dementia and Cognitive Improvement Group, Radcliffe Infirmary, Woodstock Road, Oxford, UK.

Background: Micronutrient status can affect cognitive function at all ages. Vitamin deficiencies could influence memory function and might contribute to age-associated cognitive impairment and dementia.Vitamin B6, comprising three chemically distinct compounds pyridoxal, pyridoxamine, and pyridoxine, is involved in the regulation of mental function and mood. Vitamin B6 is also an essential homocysteine re-methylation cofactor, and deficiency is associated with increase in blood homocysteine levels. Homocysteine is a risk factor for cerebrovascular disease and may also have directly toxic effects on neurons of the central nervous system. Neuropsychiatric disorders including seizures, migraine, chronic pain and depression have been linked to vitamin B6 deficiency. Epidemiological studies indicate that poor vitamin B6 status is common among older people. Hyperhomocysteinaemia has been suggested as a cause or mechanism in the development Alzheimer's disease and other forms of dementia. Supplementation with B vitamins including vitamin B6 has been shown to reduce blood homocysteine levels. Objectives: To assess the efficacy of vitamin B6 supplementation in reducing the risk of developing cognitive impairment by older healthy people, or improving cognitive functioning of people with cognitive decline and dementia, whether or not vitamin B6 deficiency has been diagnosed. Search Strategy: The Specialized Register of the Cochrane Dementia and Cognitive Improvement Group was searched on 20 May 2003 using the terms: vitamin B6, pyridoxine, pyridoxamine, pyridoxal. For relevant trials on healthy elderly people MEDLINE, EMBASE and CENTRAL were searched using the previously mentioned terms as well as the term cognit * Selection Criteria: All unconfounded, double-blind randomized controlled trials in which the intervention with vitamin B6 was compared with placebo for healthy older people or people with cognitive decline or dementia. The primary outcome of interest was the efficacy of vitamin B6 supplementation on cognitive function. Data collection and analysis: The two reviewers independently evaluated all studies identified as possibly meeting the criteria for inclusion. One reviewer independently extracted the data. Studies were rated for their overall quality. The weighted mean differences between treatment and placebo groups, with 95% confidence intervals, were calculated for each outcome. Review Manager version 4.2 was used to analyse the variance. Main Results: No trials of vitamin B6 involving people with cognitive impairment or dementia were found. The two trials included in the review (Bryan 2002; Deijen 1992) used a double-blind, randomized, placebo-controlled design and involved 109 healthy older people. One trial restricted enrolment to women and the other to men. Vitamin B6 supplementation and healthy older women: Bryan 2002 enrolled 211 healthy women from various age groups into a 5-week study. The trial was of multifactorial design with folic acid, vitamin B12, vitamin B6 and placebo in its four arms. Twelve healthy women aged 65 to 92 years received 75 mg vitamin B6 orally per day and were compared with 21 healthy women who were allocated to placebo. No statistically significant benefits from vitamin B6 on mood or cognition were observed. Vitamin B6 supplementation and healthy older men: Deijen 1992 recruited 76 healthy men aged 70 to 79 years. They were divided into 38 matched pairs, one member of each pair randomly allocated to 20 mg of vitamin B6 (pyridoxine hydrochloride) per day for 12 weeks the other to placebo. No statistically significant differences between treatment and placebo were found in their effects on cognition or mood. Effect of vitamin B6 supplementation on vitamin B6 status: Deijen 1992 reported that 20 mg of pyridoxine hydrochloride per day for 12 weeks increased blood vitamin B6 activity as assessed as by plasma pyridoxal-5'-phosphate (WMD 238, 95%CI 211.58 to 264.42, P<0.00001) and erythrocyte enzyme asparate aminotransferase (WMD 0.43, 95%CI 0.30 to 0.56, P<0.00001). Effect of vitamin B6 supplementation on blood homocysteine concentration: Neither of the included trials measured homocysteine levels. Drop-outs: All participants allocated to vitamin B6 or placebo completed the trial protocol. Adverse Events: No adverse effects were reported. Effect of vitamin B6 on carer burden, care costs and institutionalization rate: We found no trials in which these outcomes were assessed. Reviewer's conclusions: This review found no evidence for short-term benefit from vitamin B6 in improving mood (depression, fatigue and tension symptoms) or cognitive functions. For the older people included in one of the two trials included in the review, oral vitamin B6 supplements improved biochemical indices of vitamin B6 status, but potential effects on blood homocysteine levels were not assessed in either study. This review found evidence that there is scope for increasing some biochemical indices of vitamin B6 status among older people. More randomized controlled trials are needed to explore possible benefits from vitamin B6 supplementation for healthy older people and those with cognitively impairment or dementia.

Am J Clin Nutr. 1998 Feb.
Vitamin B-6 requirement and status assessment of young women fed a high-protein diet with various levels of vitamin B-6.
Huang YC, Chen W, Evans MA, Mitchell ME, Shultz TD.
Department of Food Science and Human Nutrition, Washington State University, Pullman, WA, USA.

The vitamin B-6 requirement of young women consuming a constant high-protein diet (1.55 g/kg body wt) and the effect of various ratios of vitamin B-6 to protein on this requirement were studied. Eight women were fed a lactoovovegetarian basal diet containing 0.45 mg vitamin B-6 (2.66 micromol as pyridoxine) and 30 micromol carnitine for 92 d. The protocol consisted of successive baseline adjustment (9 d), depletion (27 d), and repletion (two 21-d and then one 14-d) periods. Vitamin B-6 intakes were 1.60, 0.45, 1.26, 1.66, and 2.06 mg, resulting in ratios of vitamin B-6 (in mg) to protein (in g) for the five periods of 0.016, 0.005, 0.013, 0.017, and 0.021, respectively. Direct and indirect as well as short- and long-term vitamin B-6 status measures were assessed weekly. Regression analysis revealed that the amount of dietary vitamin B-6 required to normalize urinary 4-pyridoxic acid, plasma pyridoxal-P, erythrocyte pyridoxal-P and pyridoxal, and erythrocyte alanine and aspartate aminotransferase activity coefficients to predepletion baseline values was 1.94 mg vitamin B-6/d (0.019 mg vitamin B-6/g protein). This study suggests that the current vitamin B-6 recommended dietary allowance of 1.6 mg/d based on 0.016 mg/g protein is not an adequate intake and may require reevaluation.

J Nutr. 1996 Oct.
Vitamin B-6 status indicators decrease in women consuming a diet high in pyridoxine glucoside.
Hansen CM, Leklem JE, Miller LT.
Department of Nutrition and Food Management, Oregon State University, Corvallis, USA.

Previous research has shown that the pyridoxine glucoside (PNG) form of vitamin B-6 has a reduced bioavailability compared with pyridoxine, but its effect on vitamin B-6 status has not been assessed. Following an 8-d adjustment period, nine women consumed diets containing a high or low amount of PNG for 18 d each, in a crossover design. The high and low PNG diets provided 1.52 mg/d (8.98 micromol/d) and 1.44 mg/d (8.57 micromol/d) of vitamin B-6, of which 27% and 9% was PNG, respectively. The dietary vitamin B-6 to protein ratio of both diets was 0.017 mg/g. Urinary excretions of 4-pyridoxic acid and total vitamin B-6 were significantly lower (P < 0.05) during the high PNG diet period than when the low PNG diet was consumed. Urinary PNG excretion was equal to about 9% of the total PNG intake during both periods. Plasma total vitamin B-6 (P < 0.01) and red blood cell pyridoxal 5'-phosphate (PLP) (P < 0.05) were significantly lower when the high PNG diet was consumed than during the low PNG diet period. Fecal total vitamin B-6 excretion was significantly higher (P < 0.001) when the high PNG diet was consumed. Women consuming a diet containing a higher percentage of the total vitamin B-6 intake as PNG exhibited a decrease in vitamin B-6 status indicators, consistent with the reduced bioavailability of PNG demonstrated in other studies, equal to a loss of 15-18% of the total vitamin B-6 intake. During the determination of Recommended Dietary Allowances, the reduced bioavailability of PNG and its presence in higher amounts in some diets should be considered.

[Note: Plant foods such as wheat are high in pyridoxine glucoside.]

Pediatr Res. 1995 Nov.
Low vitamin B6 status associated with slow growth in healthy breast-fed infants.
Heiskanen K, Siimes MA, Salmenpera L, Perheentupa J.
Children's Hospital, University of Helsinki, Finland.

To evaluate the effect of vitamin B6 status on infant growth, we studied longitudinally anthropometry and the erythrocyte parameters that reflect long-term vitamin B6 status [erythrocyte pyridoxal 5'-phosphate concentration (EPLP), erythrocyte aspartate transaminase basal activity (EAST0), and its activation co-efficient (alpha EAST)] in 44 infants. The infants were exclusively breast-fed for 6 mo, given additional solids according a uniform schedule from 6-9 mo, and formula after 9 mo, if needed. In seven of these infants, a low vitamin B6 status (EPLP < 10th, and EAST0 > 10th or alpha EAST > 90th percentile for these values in reference infants) was observed between 4 and 6 mo of age. These seven infants showed slower length velocity (0.30 +/- 0.05 versus 0.40 +/- 0.02 mm/d, p < or = 0.02) and deeper fall in length-for-age (-0.69 +/- 0.20 versus -0.25 +/- 0.07 SD score, p < or = 0.03) from 6 to 9 mo of age than the similarly fed infants with higher vitamin B6 status. Preceding vitamin B6 status remained a significant explanatory factor for length velocity and change in length-for-age in addition to preceding and concomitant weight velocity, when sex, birth size, preceding length gain, and mid-parent height were taken into account. Change in weight-for-age alone explained 16% and 18% and, together with vitamin B6 status, 23 and 27% of the variation in length velocity and in change in length-for-age, respectively. Thus, in healthy breast-fed infants, according to our results, low vitamin B6 status is associated with reversibly reduced gain in length.

Am J Clin Nutr. 1990 Jun.
Distribution of B-6 vitamers in human milk during a 24-h period after oral supplementation with different amounts of pyridoxine.
Hamaker BR, Kirksey A, Borschel MW.
Department of Foods and Nutrition, Purdue University, West Lafayette, IN.

The relative distribution of B-6 vitamers, separated by reverse-phase liquid chromatography, was examined in human milk during a 24-h period after supplementation with 2.5 or 15 mg pyridoxine hydrochloride. Consistently, pyridoxal (PL) was the predominate vitamer and the most responsive to vitamin B-6 intake. During 3-8 h after supplement ingestion, PL, pyridoxal phosphate, and pyridoxamine concentrations were significantly higher than at other times examined. In the first two periods after supplementation, PL as a percentage of total vitamin B-6 was slightly but significantly higher in milk from the group supplemented with 15 mg than from the group supplemented with 2.5 mg. With the exception of PL, the distribution of B-6 vitamers, expressed as percent of total vitamin B-6, was similar for the two supplemented groups at all times examined. Percentage PL of total vitamin B-6 in milk was approximately 25% lower in unsupplemented than in supplemented women.

Am J Clin Nutr. 1986 Jan.
Effects of vitamin B6 intake on nutriture and growth of young infants.
Borschel MW, Kirksey A, Hannemann RE.

Vitamin B6 is critical to normal development; however, the requirement for adequate nutriture of the human infant is based on limited experimental data. In this study vitamin B6 intakes of breast-fed (BF) and formula-fed (FF), healthy, term infants were related to levels of pyridoxal phosphate (PLP) in their plasma at 1, 2, 4, and 6 mo of age. Mothers of BF infants were supplemented with either 2.5 or 15.0 mg pyridoxine . hydrochloride (PN . HCl)/d. Growth was similar for FF and BF infants and was within normal ranges over the 6 mo period. Plasma PLP in cord blood was similar in BF and FF infants; however, at 1-5 d of age and at each subsequent age studied, levels of plasma PLP were significantly higher in FF infants than in BF. Lowest PLP values were for BF infants of mothers who received 2.5 mg PN . HCl/d. Mean plasma PLP decreased with age and was not correlated to vitamin B6 intakes except at 1 mo of age. At this age, vitamin B6 intake of BF infants whose mothers received 2.5 mg PN . HCl/d was only 0.1 mg B6/d. The consequences of this are uncertain; however, plasma PLP levels of the infants were low and reflected their intakes of vitamin B6.

Pediatrics. 1985 Nov.
Nutritionally relevant supplementation of vitamin B6 in lactating women: effect on plasma prolactin.
Andon MB, Howard MP, Moser PB, Reynolds RD.

Pharmacologic doses of vitamin B6 administered to lactating women have been reported to suppress plasma prolactin. As a result, some physicians have recommended restriction of vitamin B6 intake for lactating women. In the present investigation, 20 lactating women were given supplemental doses of vitamin B6, 0.5 to 4.0 mg/d, beginning 24 hours after delivery. Plasma prolactin, plasma pyridoxal phosphate, and breast milk total vitamin B6 concentrations were determined during the first 9 months postpartum. Women receiving the supplement of 4.0 mg compared with 0.5 mg of vitamin B6 per day had significantly higher plasma pyridoxal phosphate (P less than .01) and breast milk total vitamin B6 concentrations (P less than .05) beginning at 1 month postpartum and continuing through the duration of the study. Plasma prolactin concentrations were not significantly different between the two groups. The percentage of all women, regardless of treatment, in whom lactation persisted at 1 and 2 weeks and 1, 3, 6, and 9 months were 100%, 100%, 100%, 90%, 80%, and 65%, respectively. All women who ceased to lactate during the study reported doing so by choice. Nutritionally relevant doses of vitamin B6 elevated plasma pyridoxal phosphate and breast milk total vitamin B6 concentrations of lactating women without reducing plasma prolactin concentration or halting lactation.