Cover Image

PAPERBACK
$47.95



View/Hide Left Panel

7
Vitamin B6

SUMMARY

Vitamin B6 (pyridoxine and related compounds) functions as a coenzyme in the metabolism of amino acids, glycogen, and sphingoid bases. The primary criterion used to estimate the Recommended Dietary Allowance (RDA) for vitamin B6 is a plasma 5'-pyridoxal phosphate value of at least 20 nmol/L. Bioavailability of 75 percent is assumed from a mixed diet. The RDA for young adults is 1.3 mg. Recently, the median intake of vitamin B6 from food in the United States was approximately 2 mg/day for men and 1.4 mg/day for women; in one Canadian population study the median intake was approximately 1.8 mg/day for men and 1.3 mg/day for women. The ninety-fifth percentile of U.S. intake from both food and supplements has been estimated to be 6 to 10 mg/ day. The critical adverse effect from high intake of the vitamin is sensory neuropathy. The data fail to demonstrate a causal association between pyridoxine intake and other endpoints (e.g., dermatological lesions and vitamin B6 dependency in newborns). The Tolerable Upper Intake Level (UL) for adults is 100 mg/day of vitamin B6.

BACKGROUND INFORMATION

Vitamin B6 (B6) comprises a group of six related compounds: pyridoxal (PL), pyridoxine (PN), pyridoxamine (PM), and their respective 5'-phosphates (PLP, PNP, and PMP). The major forms in



The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement



Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.

OCR for page 150
DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline 7 Vitamin B6 SUMMARY Vitamin B6 (pyridoxine and related compounds) functions as a coenzyme in the metabolism of amino acids, glycogen, and sphingoid bases. The primary criterion used to estimate the Recommended Dietary Allowance (RDA) for vitamin B6 is a plasma 5'-pyridoxal phosphate value of at least 20 nmol/L. Bioavailability of 75 percent is assumed from a mixed diet. The RDA for young adults is 1.3 mg. Recently, the median intake of vitamin B6 from food in the United States was approximately 2 mg/day for men and 1.4 mg/day for women; in one Canadian population study the median intake was approximately 1.8 mg/day for men and 1.3 mg/day for women. The ninety-fifth percentile of U.S. intake from both food and supplements has been estimated to be 6 to 10 mg/ day. The critical adverse effect from high intake of the vitamin is sensory neuropathy. The data fail to demonstrate a causal association between pyridoxine intake and other endpoints (e.g., dermatological lesions and vitamin B6 dependency in newborns). The Tolerable Upper Intake Level (UL) for adults is 100 mg/day of vitamin B6. BACKGROUND INFORMATION Vitamin B6 (B6) comprises a group of six related compounds: pyridoxal (PL), pyridoxine (PN), pyridoxamine (PM), and their respective 5'-phosphates (PLP, PNP, and PMP). The major forms in

OCR for page 150
DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline animal tissues are PLP and PMP; plant-derived foods contain primarily PN and PNP, sometimes in the form of a glucoside. In humans, the major excretory form is 4-pyridoxic acid (4-PA). Function PLP is a coenzyme for more than 100 enzymes involved in amino acid metabolism, including aminotransferases, decarboxylases, racemases, and dehydratases. It is a coenzyme for δ-aminolevulinate synthase, which catalyzes the first step in heme biosynthesis, and for cystathionine β-synthase and cystathioninase, enzymes involved in the transsulfuration pathway from homocysteine to cysteine. The carbonyl group of PLP binds to proteins as a Schiff’s base with the ε-amine of lysine. For practically all PLP enzymes the initial step in catalysis involves formation of a Schiff’s base between an incoming amino acid, via its α-amino group, and the carbonyl group of PLP. Much of the total PLP in the body is found in muscle bound to phosphorylase. PLP is a coenzyme in the phosphorylase reaction and is also directly involved in catalysis. Physiology of Absorption, Metabolism, and Excretion Absorption and Transport In animal tissue the major form of B6 is PLP; next is PMP. Absorption in the gut involves phosphatase-mediated hydrolysis followed by transport of the nonphosphorylated form into the mucosal cell. Transport is by a nonsaturable passive diffusion mechanism. Even extremely large doses are well absorbed (Hamm et al., 1979). PN glucoside is absorbed less effectively than are PLP and PMP and, in humans, is deconjugated by a mucosal glucosidase (Nakano and Gregory, 1997). Some PN glucoside is absorbed intact and can be hydrolyzed in various tissues. Metabolism Most of the absorbed nonphosphorylated B6 goes to the liver. PN, PL, and PM are converted to PNP, PLP, and PMP by PL kinase. PNP, which is normally found only at very low concentrations, and PMP are oxidized to PLP by PNP oxidase. PMP is also generated from PLP via aminotransferase reactions. PLP is bound to various proteins in tissues; this protects it from the action of phosphatases. The capacity for protein binding limits the accumulation of PLP by

OCR for page 150
DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline tissues at very high intakes of B6 (Merrill et al., 1984). When this capacity is exceeded, free PLP is rapidly hydrolyzed and nonphosphorylated forms of B6 are released by the liver and other tissues into circulation. At pharmacological doses of B6, the high capacities for PLP-protein binding of muscle, plasma, and erythrocytes (hemoglobin) allow them to accumulate very high levels of PLP when other tissues are saturated (Lumeng et al., 1978). PLP in the liver can be oxidized to 4-PA, which is released and excreted. The major PLP-binding protein in plasma is albumin. PLP is the major form of the vitamin in plasma and is derived entirely from liver as a PLP-albumin complex (Fonda et al., 1991; Leklem, 1991). Tissues and erythrocytes can transport nonphosphorylated forms of the vitamin from plasma. Some of this is derived from plasma PLP after phosphatase action. In tissues, conversion of the transported vitamin to PLP, coupled with protein binding, allows accumulation and retention of the vitamin. B6 in tissues is found in various subcellular compartments but primarily in the mitochondria and the cytosol. Excretion Normally, the major excretory product is 4-PA, which accounts for about half the B6 compounds in urine (Shultz and Leklem, 1981). Other forms of the vitamin are also found in urine. With large doses of B6, the proportion of the other forms of the vitamin increases. At very high doses of PN, much of the dose is excreted unchanged in the urine. B6 is also excreted in feces but probably to a limited extent (Lui et al., 1985). Microbial synthesis of B6 in the lower gut makes it difficult to evaluate the extent of this excretion. Body Stores Pharmacokinetic analyses of urinary excretion of a tracer dose of labeled PN and its metabolites have suggested a two-compartment model for body B6 stores (Johansson et al., 1966). With this approach, body stores have been estimated at 365 µmol (61 mg) or 7.7 µmol/kg in a healthy 20-year-old woman and 660 µmol (110 mg) or 8.8 µmol/kg in a 25-year-old man. Overall body half-lives were about 25 days (Shane, 1978). Intake (and excretion) was estimated to be 1.5 mg (9 µmol) for the woman and 3.4 mg (20 µmol) for the man. The two-compartment model has been questioned because muscle stores most of the body’s B6; the pool in muscle appears to turn over very slowly. This fact may have not been considered, resulting

OCR for page 150
DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline in a substantial underestimation of body stores. Coburn and colleagues (1988a) estimated the B6 content of muscle biopsies and, by assuming that muscle represented 80 percent of the body B6 store, calculated a total body store of about 1,000 µmol (167 mg). Extrapolation of data from studies with experimental animals to assess the B6 requirement for maintenance and growth (Coburn et al., 1987, 1988b) indicates that 1 mg of PN would be an adequate intake for the adult. Modeling of human B6 pools has also led to an assessment of a minimum requirement of about 0.4 mg/day of PN (Coburn, 1990). Clinical Effects of Inadequate Intake The classical clinical symptoms of B6 deficiency are a seborrheic dermatitis (Mueller and Vilter, 1950), microcytic anemia (Snyderman et al., 1953), epileptiform convulsions (Bessey et al., 1957; Coursin, 1954), and depression and confusion (Hawkins and Barsky, 1948). Microcytic anemia reflects decreased hemoglobin synthesis. The first enzyme and committed step in heme biosynthesis, aminolevulinate synthase, uses PLP as a coenzyme. Because PLP is also a coenzyme of decarboxylases that are involved in neurotransmitter synthesis, defects in some of these enzymes could explain the onset of convulsions in B6 deficiency. Many studies have demonstrated that the levels of neurotransmitters such as dopamine, serotonin, and γ-aminobutyrate are reduced in B6-depleted experimental animals, especially in extreme B6 depletion (Dakshinamurti and Stephens, 1969; Dakshinamurti et al., 1991, 1993; Sharma and Dakshinamurti, 1992; Sharma et al., 1994; Stephens et al., 1971). Some of these studies were reviewed in a conference report (Dakshinamurti, 1990). However, it has not been definitely shown whether the convulsions are due to the reduced level of one of these neurotransmitters in particular. Guilarte (1993) proposed that the convulsions are caused by abnormal tryptophan metabolites that accumulate in the brain in B6 deficiency. Electroencephalogram (EEG) abnormalities have also been reported in controlled studies of B6 depletion. In one depletion-repletion study (Kretsch et al., 1991) 2 of 11 young women placed on a diet containing less than 0.05 mg of B6 exhibited abnormal EEG patterns within 12 days. The abnormal patterns were promptly corrected by 0.5 mg/day of PN. Similar abnormalities were reported in young men placed on a diet containing less than 0.06 mg/day of B6 for 21 days (Canham et al., 1964). However, no EEG changes were detected when young men were placed on a diet containing

OCR for page 150
DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline 0.16 mg/day of B6 for 21 days (Grabow and Linkswiler, 1969). Although a longer depletion period with 0.16 mg/day of B6 may have eventually resulted in some abnormalities, diets containing 0.5 mg/ day of B6 have consistently failed to demonstrate abnormal EEG patterns or any hematological symptoms. Convulsions and dermatitis were not seen in these studies. Inadequate intakes of B6 have also been reported to impair platelet function and clotting mechanisms (Brattstrom et al., 1990; Subbarao and Kakkar, 1979), but these effects may also be due to the hyperhomocysteinemia noted in such patients (Brattstrom et al., 1990). SELECTION OF INDICATORS FOR ESTIMATING THE REQUIREMENT FOR VITAMIN B6 Indicators of vitamin B6 status have traditionally been described as direct (vitamin concentrations in plasma, blood cells, or urine), indirect, or as functional (erythrocyte aminotransferase saturation by pyridoxal 5'-phosphate [PLP] or tryptophan metabolites). In most instances, the concentrations of these indicators change with increases or decreases in vitamin intake. As such, they are useful as indicators of relative B6 status, especially in controlled depletion-repletion studies (Leklem, 1990; Sauberlich et al., 1972). However, there is little scientific information concerning which concentration of a particular indicator represents a clinical deficiency or inadequate status of the vitamin. Because of this, B6 requirements have often been evaluated by using a combination of status indicators. However, this does not overcome the problem of establishing absolute values reflecting impaired status. The increase in methionine metabolites after a methionine load has also been used as an indicator of B6 status (Leklem, 1994) but it has not found extensive use in B6 requirement studies. A review of established indicators of B6 status suggests that plasma PLP is probably the best single indicator because it appears to reflect tissue stores (Lui et al., 1985). Plasma Pyridoxal 5'-Phosphate The plasma PLP concentration reflects liver PLP (Lumeng and Li, 1974) and changes fairly slowly in response to changes in vitamin intake, taking about 10 days to reach a new steady state (Lui et al., 1985). The plasma PLP concentration generally correlates with other indices of B6 status. PLP is the major form of B6 in tissues and

OCR for page 150
DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline is the active coenzyme species. In animals fed graded levels of pyridoxine (PN), the plasma PLP concentration correlated well with tissue B6 (Lumeng et al., 1978). Protein-bound PLP in the plasma is in equilibrium with free PLP. Binding of PLP to protein protects it from hydrolysis by alkaline phosphatase. Conditions of increased plasma phosphatase activity can lead to reduced plasma PLP. Hydrolysis of plasma PLP is required before it can be transported into tissues. In the controlled depletion-repletion study (Kretsch et al., 1991) in which 2 of 11 young women placed on a diet containing less than 0.05 mg of B6 exhibited abnormal electroencephalogram patterns, plasma PLP dropped to about 9 nmol/L. Similar PLP values were also observed in the other 9 depleted but asymptomatic subjects. This suggests that PLP concentrations of about 10 nmol/L represent a suboptimal concentration associated with clinical consequences in some subjects. Although fewer than half the subjects in this study exhibited signs of deficiency, more subjects might have shown signs if the depletion diet had been continued longer than 12 days. Leklem (1990) has suggested a plasma PLP concentration of 30 nmol/L as the lower end of normal status. Results from a large number of studies involving various population groups (Brown et al., 1975; Driskell and Moak, 1986; Lindberg et al., 1983; Lumeng et al., 1974; Miller et al., 1975, 1985; Rose et al., 1976; Tarr et al., 1981) have shown that a substantial proportion of individuals in these populations, in some cases half, have plasma PLP concentrations below 30 nmol/L, but there are no confirming clinical or other data to suggest B6 deficiency. Other investigators have proposed a cutoff of 20 nmol/L for plasma PLP as an index of adequacy (Lui et al., 1985). The more conservative cutoff of 20 nmol/L is not accompanied by observable health risks but it allows a moderate safety margin to protect against the development of signs or symptoms of deficiency. A cutoff for PLP of 20 nmol/L was selected as the basis for the average requirement (EAR) for B6 although its use may overestimate the B6 requirement for health maintenance of more than half the group. A recent random sampling of the Dutch population indicated a 3 to 7 percent prevalence of plasma PLP concentrations of less than 19 nmol/L in various life stage and gender groups (Brussaard et al., 1997a, b). The prevalence was slightly higher in men aged 50 to 79 years. Although plasma PLP values in this population correlated with dietary variables, some of the fundamental tests for B6 status,

OCR for page 150
DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline including the increase in homocysteine after a methionine load, did not correlate as well. Plasma PLP concentrations decrease slightly with increased protein intake. They are very high by comparison in the fetus, decrease fairly rapidly in the first year, and then decrease more gradually throughout the lifespan (Hamfelt and Tuvemo, 1972). It is not possible to evaluate whether the higher values in newborns and infants reflect ample body stores or whether the higher concentrations reflect normal status for this age group. Because of this, it is not possible to state that a 20 nmol/L concentration in the infant reflects a status equivalent to that for a 20 nmol/L PLP concentration in the adult. Normally, plasma PLP is measured by using an apotyrosine decarboxylase assay. This assay has been well standardized and there is usually good interlaboratory agreement with it. Erythrocyte and Total Blood Pyridoxal 5'-Phosphate Erythrocyte and total blood PLP concentrations have also been used as measures of B6 status but not as extensively as plasma PLP. Erythrocyte PLP concentrations are similar to those for plasma PLP in individuals on normal diets, but they increase to much higher values than does plasma PLP in subjects taking large doses of the vitamin (Bhagavan et al., 1975). This reflects the high binding capacity of hemoglobin for PLP. Erythrocyte PLP is derived from plasma pyridoxal (PL); the erythrocyte contains PL kinase activity. Because of lower kinase activity, blacks may have lower erythrocyte PLP values than do whites. The small number of studies using erythrocyte values limits the ability to derive a concentration consistent with adequate status. Blood Total Vitamin Concentrations Blood concentrations of total vitamers of B6 as well as individual concentrations of specific B6 vitamers have been determined in some studies. These values tend to fluctuate considerably. They also fluctuate throughout the menstrual cycle, which limits their usefulness as status indicators (Contractor and Shane, 1968). Urinary Pyridoxic Acid and Total Vitamin B6 Urinary B6 excretion and 4-pyridoxic acid (4-PA) excretion have been used extensively to evaluate B6 requirements. Approximately

OCR for page 150
DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline 50 percent of the B6 intake is excreted as 4-PA, but this proportion can vary somewhat. 4-PA excretion responds almost immediately to changes in dietary B6 intake (Lui et al., 1985). Because it reflects recent intake, it is of essentially no value in assessing status. Leklem (1990) has suggested a value of greater than 3 µmol/day as indicative of adequate status. This is achieved with intakes of about 1 mg of B6. However, the use of this cutoff value represents a circular argument; it presupposes that 1 mg/day of B6 is an adequate intake. Erythrocyte Aspartate Aminotransferase and Alanine Aminotransferase The stimulation (activation) of erythrocyte aspartate aminotransferase (α-EAST) and erythrocyte alanine aminotransferase (α-EALT) by PLP has been used extensively to evaluate long-term B6 status. These tests measure the amount of enzyme in the apoenzyme form; the ratio of the apoenzyme to total enzyme increases with B6 depletion. Leklem (1990) has suggested an α-EAST of less than 1.6 and an α-EALT of less than 1.25 as indicative of adequate B6 status. Variations in values reported in different studies, which may reflect blood storage conditions and time, have interfered with the setting of a well-documented cutoff point. As described in the later section “Women Ages 19 through 50 Years,” aminotransferase activation factors stabilize slowly in response to changes in diet; this leads to an overestimation of the amount of B6 required to return values to a preset value in depletion-repletion studies. The absolute EALT and EAST enzyme activities, both holo- and total enzyme, have also been measured in many studies, but the large variation in values limits their usefulness as indicators of status (Raica and Sauberlich, 1964). Tryptophan Catabolites One of the earliest markers for B6 deficiency was the urinary excretion of xanthurenic acid, which is normally a minor tryptophan catabolite. The major pathway of tryptophan catabolism proceeds via the PLP-dependent kynureninase reaction (Shane and Contractor, 1980). The xanthurenic acid pathway also involves PLP-dependent enzymes. However, under conditions of B6 deficiency, this minor pathway is used to a greater extent, leading to the increased excretion of abnormal tryptophan metabolites. Mitochondrial enzymes involved in xanthurenic acid production probably retain their

OCR for page 150
DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline PLP more effectively than does the cytosolic kynureninase under these conditions. The evaluation of B6 status by measuring tryptophan catabolites after a loading dose of tryptophan has been used extensively to assess B6 status. Various challenge doses of tryptophan have been used in different studies. Xanthurenic acid excretion is responsive to B6 intake in controlled depletion-repletion studies. However, as for many of the tests of B6 status, it is not clear what level of excretion represents adverse B6 status under the conditions of the tryptophan challenge dose. Leklem (1990) has suggested that a 24-hour urinary excretion of less than 65 µmol xanthurenate after a 2-g tryptophan oral dose indicates normal B6 status. The first enzyme in the tryptophan catabolic pathway is a dioxygenase that is induced by various steroid hormones. Consequently, the flux through this pathway and the excretion of minor tryptophan catabolites can be influenced by conditions of changed hor-monal status. For example, both pregnancy and the use of highdose oral contraceptive agents increase the excretion of these catabolites (Rose, 1978) (see “Oral Contraceptive Agents”). Plasma Homocysteine Homocysteine catabolism proceeds via transsulfuration to cysteine and involves two PLP-dependent enzymes. Homocysteine can also be remethylated to methionine via folate and vitamin B12-dependent enzymes. Thus, plasma concentrations of homocysteine are influenced by B6 and folate and, to a lesser extent, B12 intakes (Selhub et al., 1993). Racial and gender differences in homocysteine values and response to vitamin intervention have been found in some studies (Ubbink et al., 1995). In a South African comparison of black and white subjects with similar lifestyles and folate and vitamin B12 status, plasma PLP concentrations were significantly lower in the black subjects; fasting plasma homocysteine concentration was similar. The increase in plasma homocysteine concentration after a methionine load was significantly less in the black subjects despite their lower plasma PLP values (Ubbink et al., 1995). After 6 weeks of daily supplementation with a multivitamin containing 10 mg of PN, 1 mg of folate, and 0.4 mg of vitamin B12, fasting homocysteine concentration decreased in both groups. The elevation in plasma homocysteine concentration after a methionine load was unaffected by supplementation in the black subjects whereas the elevation in the white subjects decreased to about the same level as observed in the black subjects. These data suggest that

OCR for page 150
DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline despite apparently lower B6 status, as indicated by plasma PLP levels, the black subjects were more efficient than the whites in catalyzing the transsulfuration of homocysteine to cysteine. The increase in plasma homocysteine concentration after a methionine load or a meal is responsive to and primarily affected by B6 status, but data are not sufficient to support using this as the criterion on which to base the EAR. Because the fasting homocysteine concentration is primarily responsive to folate status (Ubbink et al., 1996), it is not a good candidate for use in setting the EAR. Results from population-based studies using data adjusted for folate and B12 status and for age indicate that B6 status as measured by PLP is inversely correlated with nonfasting plasma homocysteine concentration (Selhub et al., 1993). At least part of the increase in plasma homocysteine concentration that occurs with aging may be due to decreased renal function (Hultberg et al., 1993) rather than B6 status. Possible Reduction of Chronic Disease Risk Moderate hyperhomocysteinemia was identified recently as a possible risk factor for vascular disease (Selhub et al., 1995; see also Chapter 8), and vitamin intervention can be used to reduce plasma homocysteine values. A recent prospective observational study has examined the effect of self-selection for intake of folate and B6 on the incidence of myocardial infarction (MI) and fatal coronary heart disease (CHD) (Rimm et al., 1998). After other risk factors for CHD were controlled for and vitamin intake was adjusted for energy intake, about a twofold reduction in MI and CHD was found for individuals in the quintile with the highest folate and B6 intakes compared with those with the lowest intakes. When intakes of each of the vitamins were considered separately, the multivariate analyses suggested about a 30 percent reduction in disease incidence between individuals in the highest and lowest quintiles of intake for each of the vitamins. For B6 the data are compatible with the Framingham study (Selhub et al., 1993), in which the lowest deciles of B6 intake were associated with higher circulating homocysteine. However, in the current study although multivariate analysis indicated a trend in risk reduction across the quintiles of intake, the major reduction appeared to occur between the fourth and fifth quintiles of intake (median intakes 2.7 and 4.6 mg). At these high B6 intakes, there is little effect of B6 intake on homocysteine levels, which are mainly affected by changes in intake at much lower intakes. Although these data are intriguing and suggest that self-

OCR for page 150
DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline selection for high B6 intake may lower CHD incidence, the highest quintile of intake was associated with increased supplement use. Some of these individuals may also exhibit other lifestyle differences that influence CHD risk, some of which were not and others that could not have been considered in the analysis. In addition, vitamin intakes were normalized to energy intake, which may have had an effect. A study of elderly patients with coronary disease indicated a significantly elevated plasma homocysteine concentration compared with control subjects; homocysteine values were inversely correlated with plasma vitamin concentrations (Robinson et al., 1995). Plasma PLP values below 20 nmol/L were seen in 10 percent of the patients but in only 2 percent of the control subjects (p < 0.01). Studies of B6-homocysteine-vascular disease relationships were not considered in this analysis if conducted with patients with end-stage renal disease. Because homocysteine is metabolized in the kidney, this condition would exacerbate any effects of vitamin deficiency. Kidney disease may also affect B6 metabolism and turnover. Several ongoing randomized trials are addressing whether supplementation will decrease risks of CHD. Thus, it would be premature to establish a B6 intake level and corresponding homocysteine value for lowest risk for disease. Cognitive Function The relationship of vitamin status to cognitive function was recently evaluated in the elderly (Riggs et al., 1996). B6 status, as evaluated by plasma PLP concentrations, was related to 2 out of a battery of about 20 tests. The usefulness of these tests for evaluating B6 status will require further validation of the putative relationships. FACTORS AFFECTING THE VITAMIN B6 REQUIREMENT Bioavailability Vitamin B6 bioavailability was recently reviewed by Gregory (1997). B6 in a mixed diet is about 75 percent bioavailable (Tarr et al., 1981). A mixed diet typically contains about 15 percent pyridoxine (PN) glucoside (Gregory, 1997), which is about 50 percent as bioavailable as the other B6 vitamins. The bioavailability of nonglucoside forms of the vitamin is greater than 75 percent. The absorption of B6 compounds in the absence of food is comparable, even at very high doses. About 70 percent of a loading dose

OCR for page 150
DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline show that two patients who took 500 mg/day of pyridoxine for 8 and 36 months developed sensory neuropathy and as did one patient who took 100 to 200 mg/day for 36 months. This finding conflicts with the weight of evidence showing that daily doses in the range of 100 to 200 mg are not associated with the development of this condition. It is not clear from the report whether the neurological symptoms of the patient taking 100 to 200 mg/day were confirmed by a clinical neurological examination. The report notes that clinical neurological examinations were performed on about half of the patients. In addition, the report notes that electrophysiological studies were performed on seven patients and sural nerve biopsies were performed on two patients. It is not clear from the report which patients were examined clinically and which received additional tests. A local television report publicizing this syndrome before the study may have biased the selection of patients and reporting of neurological symptoms. Two additional studies that report sensory neuropathy at doses of less than 200 mg/day (Dalton, 1985; Dalton and Dalton, 1987) warrant examination. In a letter to the editor, Dalton (1985) reported sensory neuropathy (characterized as burning, shooting, and tingling pains; paresthesia of limbs; clumsiness, ataxia; or perioral numbness) in 23 of 58 women (40 percent) being treated with 50 to 300 mg/day of pyridoxine for premenstrual syndrome. This case report contains methodological flaws including lack of information on the duration of treatment, use of other medications or herbal preparations, and lack of confirmatory information on actual doses consumed. In a subsequent publication, which may have included patients from the earlier case report (Dalton, 1985), Dalton and Dalton (1987) retrospectively studied 172 women who were attending a private practice specializing in premenstrual syndrome and who were reported to have taken 50 to 500 mg/day of pyridoxine. The subjects were divided into two groups: 103 women who complained of neurological symptoms and 69 who did not. Neurological symptoms were not adequately detailed in this study. In addition, the actual doses may be underestimated because the patients were also taking vitamin supplements. In summary, the weaknesses of this study and the inconsistency of the results with the weight of evidence pertaining to the safety of higher doses of pyridoxine rule out the use of these data to determine a UL.

OCR for page 150
DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline Uncertainty Assessment. An uncertainty factor (UF) of 2 was selected based on the limitations of the data involving pyridoxine doses of less than 500 mg/day. Derivation of a UL. The NOAEL of 200 mg/day was divided by the UF of 2 to obtain a UL of 100 mg/day for adults: B6 UL Summary, Ages 19 Years and Older UL for Adults 19 years and older 100 mg/day of vitamin B6 as pyridoxine Other Life Stage Groups Some concern for pregnant and lactating women could arise from the data available in the literature on congenital defects, B6 dependency, and antilactogenic effects (Donaldson and Bury, 1982; Foukas, 1973; Gardner et al., 1985; Hunt et al., 1954; Marcus, 1975; Philpot et al., 1995; Scaglione and Vecchione, 1982). Scientifically based, controlled studies designed to assess the potential adverse effects of pyridoxine intake by pregnant and lactating women are lacking. As noted above, the weight of the evidence from controlled studies in animals during pregnancy reveals no adverse effects related to teratogenicity, and the evidence from humans reveals no adverse effects from intakes up to 200 mg/day. Therefore, a UL of 100 mg/day was set for pregnant and lactating women as well. The ULs for children and adolescents were calculated from the UL for adults by using the method described in Chapter 3; this method adjusts for body size. B6 UL Summary, Ages 1 through 18 Years, Pregnancy, Lactation UL for Infants 0–12 months Not possible to establish; source of intake should be formula and food only

OCR for page 150
DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline UL for Children 1–3 years 30 mg/day of vitamin B6 as pyridoxine 4–8 years 40 mg/day of vitamin B6 as pyridoxine 9–13 years 60 mg/day of vitamin B6 as pyridoxine UL for Adolescents 14–18 years 80 mg/day of vitamin B6 as pyridoxine UL for Pregnancy 14–18 years 80 mg/day of vitamin B6 as pyridoxine 19 years and older 100 mg/day of vitamin B6 as pyridoxine UL for Lactation 14–18 years 80 mg/day of vitamin B6 as pyridoxine 19 years and older 100 mg/day of vitamin B6 as pyridoxine Special Considerations A review of the literature failed to identify special subgroups that are distinctly susceptible to sensory neuropathy after excess pyridoxine intake. Intake Assessment Based on data from the Third National Health and Nutrition Survey (Appendix H), 9 mg/day was the highest mean intake of B6 from food and supplements reported for any life stage and gender group; this was the reported intake of pregnant females aged 14 through 55 years. The highest reported intake at the ninety-fifth percentile was 21 mg/day in pregnant females aged 14 through 55 years, most of which is pyridoxine from supplements. B6 (pyridoxine) is available over the counter in many dosages ranging up to 100 mg or more. Risk Characterization The risk of adverse effects resulting from excess intake of B6 from food and supplements appears to be very low at the highest intakes noted above. Increased risks are likely to result from large intakes of PN used to treat conditions such as carpal tunnel syndrome, painful neuropathies, seizures, premenstrual syndrome, asthma, and sickle cell disease. The UL is not meant to apply to individuals who are being treated with PN under close medical supervision.

OCR for page 150
DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline RESEARCH RECOMMENDATIONS FOR VITAMIN B6 Priority should be given to studies useful for setting Estimated Average Requirements (EARs) for vitamin B6 for children, adolescents, pregnant and lactating women, and the elderly. Future studies should be designed around the EAR paradigm, use graded levels of nutrient intake and clearly defined cutoff values for clinical adequacy and inadequacy, and be conducted for a sufficient duration. To do this, close attention should be given to the identification of indicators on which to base B6 requirements. REFERENCES Andon MB, Reynolds RD, Moser-Veillon PB, Howard MP. 1989. Dietary intake of total and glycosylated vitamin B6 and the vitamin B6 nutritional status of unsupplemented lactating women and their infants. Am J Clin Nutr 50:1050– 1058. Baer RL. 1984. Cutaneous skin changes probably due to pyridoxine abuse. J Am Acad Dermatol 10:527–528. Baker EM, Canham JE, Nunes WT, Sauberlich HE, McDowell ME. 1964. Vitamin B6 requirement for adult men. Am J Clin Nutr 15:59–66. Barnard HC, de Kock JJ, Vermaak WJ, Potgieter GM. 1987. A new perspective in the assessment of vitamin B6 nutritional status during pregnancy in humans. J Nutr 117:1303–1306. Berger A, Schaumburg HH. 1984. More on neuropathy from pyridoxine abuse. N Engl J Med 311:986–987. Bernstein AL, Lobitz CS. 1988. A clinical and electrophysiologic study of the treatment of painful diabetic neuropathies with pyridoxine. In: Leklem JE, Reynolds RD, eds. Clinical and Physiological Applications of Vitamin B6. Current Topics in Nutrition and Disease. New York: Alan R.Liss. Pp. 415–423. Bessey OA, Adam DJ, Hansen AE. 1957. Intake of vitamin B6 and infantile convulsions: A first approximation of requirements of pyridoxine in infants. Pediatrics 20:33–44. Bhagavan HN. 1985. Interaction between vitamin B6 and drugs. In: Reynolds RD, Leklem JE, eds. Vitamin B6: Its Role in Health and Disease. New York: Liss. Pp. 401–415. Bhagavan HN, Coleman M, Coursin DB. 1975. The effect of pyridoxine hydrochloride on blood serotonin and pyridoxal phosphate contents in hyperactive children. Pediatrics 55:437–441. Borschel MW. 1995. Vitamin B6 in infancy: Requirements and current feeding practices. In: Raiten DJ, ed. Vitamin B6 Metabolism in Pregnancy, Lactation and Infancy. Boca Raton, FL: CRC Press. Pp. 109–124. Borschel MW, Kirksey A, Hanneman RE. 1986. Effects of vitamin B6 intake on nutriture and growth of young infants. Am J Clin Nutr 43:7–15. Brattstrom LE, Israelsson B, Norrving B, Bergkvist D, Thorne J, Hultberg B, Hamfelt A. 1990. Impaired homocysteine metabolism in early-onset cerebral and peripheral occlusive arterial disease. Effects of pyridoxine and folic acid treatment. Atherosclerosis 81:51–60. Bredesen E, Parry GJ. 1984. Pyridoxine neuropathy. Neurology 34:136.

OCR for page 150
DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline Brophy MH, Siiteri PK. 1975. Pyridoxal phosphate and hypertensive disorders of pregnancy. Am J Obstet Gynecol 121:1075–1079. Brown RR, Rose DP, Leklem JE, Linkswiler H, Anand R. 1975. Urinary 4-pyridoxic acid, plasma pyridoxal phosphate, and erythrocyte aminotransferase levels in oral contraceptive users receiving controlled intakes of vitamin B6. Am J Clin Nutr 28:10–19. Brush MG, Bennett T, Hansen K. 1988. Pyridoxine in the treatment of premenstrual syndrome: A retrospective survey in 630 patients. Br J Clin Pract 42:448– 452. Brussaard JH, Lowik MR, van den Berg H, Brants HA, Bemelmans W. 1997a. Dietary and other determinants of vitamin B6 parameters. Eur J Clin Nutr 51:S39– S45. Brussaard JH, Lowik MR, van den Berg H, Brants HA, Kistemaker C. 1997b. Micronutrient status, with special reference to vitamin B6. Eur J Clin Nutr 51:S32– S38. Canham JE, Nunes WT, Eberlin EW. 1964. Electroencephalographic and central nervous system manifestations of vitamin B6 deficiency and induced vitamin B6 dependency in normal human adults. In: Proceedings of the Sixth International Congress on Nutrition. Edinburgh: E & S Livingstone. Cleary RE, Lumeng L, Li TK. 1975. Maternal and fetal plasma levels of pyridoxal phosphate at term: Adequacy of vitamin B6 supplementation during pregnancy. Am J Obstet Gynecol 121:25–28. Coburn SP. 1990. Location and turnover of vitamin B6 pools and vitamin B6 requirements of humans. Ann NY Acad Sci 585:76–85. Coburn SP, Mahuren JD, Szadkowska Z, Schaltenbrand WE, Townsend DW. 1987. Kinetics of vitamin B6 metabolism examined in minature swine by continuous administration of labelled pyridoxine. In: Canolty NL, Caine TP, eds. Proceedings of the 1985 Conference on Mathematical Models in Experimental Nutrition. Athens: University of Georgia. Pp. 99–111. Coburn SP, Lewis DL, Fink WJ, Mahuren JD, Schaltenbrand WE, Costill DL. 1988a. Human vitamin B6 pools estimated through muscle biopsies. Am J Clin Nutr 48:291–294. Coburn SP, Mahuren JD, Kennedy MS, Schaltenbrand WE, Sampson DA, O’Connor DK, Snyder DL, Wostmann BS. 1988b. B6 vitamin content of rat tissues measured by isotope tracer and chromatographic methods. Biofactors 1:307–312. Cohen M, Bendich A. 1986. Safety of pyridoxine—A review of human and animal studies. Toxicol Lett 34:129–139. Contractor SF, Shane B. 1968. Estimation of vitamin B6 compounds in human blood and urine. Clin Chim Acta 21:71–77. Contractor SF, Shane B. 1970. Blood and urine levels of vitamin B6 in the mother and fetus before and after loading of the mother with vitamin B6. Am J Obstet Gynecol 107:635–640. Contractor SF, Shane B. 1971. Metabolism of [14C] pyridoxol in the pregnant rat. Biochim Biophys Acta 230:127–136 Coursin DB. 1954. Convulsive seizures in infants with pyridoxine-deficient diet. JAMA 154:406–408. Crozier PG, Cordain L, Sampson DA. 1994. Exercise-induced changes in plasma vitamin B-6 concentrations do not vary with exercise intensity. Am J Clin Nutr 60:552–558. Dakshinamurti K, ed. 1990. Vitamin B6. Ann NY Acad Sci 585:1–570.

OCR for page 150
DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline Dakshinamurti K, Stephens MC. 1969. Pyridoxine deficiency in the neonatal rat. J Neurochem 6:1515–1522. Dakshinamurti K, Sharma SK, Sundaram M. 1991. Domoic acid induced seizure activity in rats. Neurosci Lett 127:193–197. Dakshinamurti K, Sharma SK, Sundaram M, Watanabe T. 1993. Hippocampal changes in developing postnatal mice following intrauterine exposure to domoic acid. J Neurosci 13:4486–4495. Dalton K. 1985. Pyridoxine overdose in premenstrual syndrome. Lancet 1168–1169. Dalton K, Dalton MJT. 1987. Characteristics of pyridoxine overdose neuropathy syndrome. Acta Neurol Scand 76:8–11. Del Tredici AM, Bernstein AL, Chinn K. 1985. Carpal tunnel syndrome and vitamin B6 therapy. In: Reynolds RD, Leklem JE, eds. Vitamin B6: Its Role in Health and Disease. Current Topics in Nutrition and Disease. New York: Alan R.Liss. Pp. 459–462. De Zegher F, Przyrembel H, Chalmers RA, Wolff ED, Huijmans JG. 1985. Successful treatment of infantile type I primary hyperoxaluria complicated by pyridoxine toxicity. Lancet 17:392–393. Donaldson GL, Bury RG. 1982. Multiple congenital abnormalities in a newborn boy associated with maternal use of fluphenazine enanthate and other drugs during pregnancy. Acta Paediatr Scand 71:335–338. Dorsey CW. 1949. The use of pyridoxine and suprarenal cortex combined in the treatment of the nausea and vomiting of pregnancy. Am J Obstet Gynecol 58:1073–1078. Dreon DM, Butterfield GE. 1986. Vitamin B6 utilization in active and inactive young men. Am J Clin Nutr 43:816–824. Driskell JA, Moak SW. 1986. Plasma pyridoxal phosphate concentrations and coenzyme stimulation of erythrocyte alanine aminotransferase activities of white and black adolescent girls. Am J Clin Nutr 43:599–603. Driskell JA, Clark AJ, Bazzarre TL, Chopin LF, McCoy H, Kenney MA, Moak SW. 1985. Vitamin B6 status of southern adolescent girls. J Am Diet Assoc 85:46–49. Driskell JA, Clark AJ, Moak SW. 1987. Longitudinal assessment of vitamin B6 status in Southern adolescent girls. J Am Diet Assoc 87:307–310. Driskell JA, McChrisley B, Reynolds LK, Moak SW. 1989. Plasma pyridoxal 5'-phosphate concentrations in obese and nonobese black women residing near Petersburg, VA. Am J Clin Nutr 50:37–40. Ellis JM. 1987. Treatment of carpal tunnel syndrome with vitamin. South Med J 80:882–884. Ellis J, Folkers K, Watanabe T, Kaji M, Saji S, Caldwell JW, Temple CA, Wood FS. 1979. Clinical results of a cross-over treatment with pyridoxine and placebo of the carpal tunnel syndrome. Am J Clin Nutr 32:2040–2046. Fogelholm M. 1992. Micronutrient status in females during a 24-week fitness-type exercise program. Ann Nutr Metab 36:209–218. Fonda ML, Trauss C, Guempel UM. 1991. The binding of pyridoxal 5'-phosphate to human serum albumin. Arch Biochem Biophys 288:79–86. Foukas MD. 1973. An antilactogenic effect of pyridoxine. J Obstet Gynaecol Br Commonw 80:718–720. Friedman MA, Resnick JS, Baer RL. 1986. Subepidermal vesicular dermatosis and sensory peripheral neuropathy caused by pyridoxine abuse. J Am Acad Dermatol 14:915–917. Fries ME, Chrisley BM, Driskell JA. 1981. Vitamin B6 status of a group of preschool children. Am J Clin Nutr 34:2706–2710.

OCR for page 150
DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline Gardner LI, Welsh-Sloan J, Cady RB. 1985. Phocomelia in infant whose mother took large doses of pyridoxine during pregnancy. Lancet 1:636. Gaynor R, Dempsey WB. 1972. Vitamin B6 enzymes in normal and pre-eclamptic human placentae. Clin Chim Acta 37:411–416. Grabow JD, Linkswiler H. 1969. Electroencephalographic and nerve-conduction studies in experimental vitamin B6 deficiency in adults. Am J Clin Nutr 22:1429– 1434 . Gregory JF 3rd. 1997. Bioavailability of vitamin B6. EUT J Clin Nutr 51:S43-S48. Guilarte TR. 1993. Vitamin B6 and cognitive development: Recent research findings from human and animal studies. Nutr Rev 51:193–198. Hamfelt A, Tuvemo T. 1972. Pyridoxal phosphate and folic acid concentration in blood and erythrocyte aspartate aminotransferase activity during pregnancy. Clin Chin Acta 41:287–298. Hamm MW, Mehansho H, Henderson LM. 1979. Transport and metabolism of pyridoxamine and pyridoxamine phosphate in the small intestine of the rat. J Nutr 109:1552–1559. Hansen CM, Leklem JE, Miller LT. 1996a. Vitamin B-6 status indicators decrease in women consuming a diet high in pyridoxine glucoside. J Nutr 126:2512–2518. Hansen CM, Leklem JE, Miller LT. 1996b. Vitamin B-6 status of women with a constant intake of vitamin B-6 changes with three levels of dietary protein. J Nutr 126:1891–1901. Hansen CM, Leklem JE, Miller LT. 1997. Changes in vitamin B-6 status indicators of women fed a constant protein diet with varying levels of vitamin B-6. Am J Clin Nutr 66:1379–1387. Hart BF, McConnell WT. 1943. Vitamin B factors in toxic psychosis of pregnancy and the puerperium. Am J Obstet Gynecol 46:304. Hawkins WW, Barsky J. 1948. An experiment on human vitamin B6 deprivation. Science 108:284–286. Heiskanen K, Salmenperä L, Perheentupa J, Siimes MA. 1994. Infant vitamin B-6 status changes with age and with formula feeding. Am J Clin Nutr 60:907–910. Heiskanen K, Kallio M, Salmenperä L, Siimes MA, Ruokonen I, Perheentupa J. 1995. Vitamin B-6 status during childhood: Tracking from 2 months to 11 years of age. J Nutr 125:2985–2992. Hendrickx AG, Cukierski M, Prahalada S, Janos Booher S, Nyland T. 1985. Evaluation of bendectin embryotoxicity nonhuman primates: II. Double-blind study term cynomolgus monkeys. Teratology 32:191–194. Huang Y-C, Chen W, Evans MA, Mitchell ME, Shultz TD. 1998. Vitamin B6 requirement and status assessment of young women fed a high-protein diet with various levels of vitamin B-6. Am J Clin Nutr 67:208–220. Hultberg B, Andersson A, Sterner G. 1993. Plasma homocysteine in renal failure. Clin Nephrol 40:230–235. Hunt AD Jr, Stokes J Jr, McCrory WW, Stroud HH. 1954. Pyridoxine dependency: Report of a case of intractable convulsions in an infant controlled by pyridoxine. Pediatrics 13:140–145. Johansson S, Lindstedt S, Register U, Wadstrom L. 1966. Studies on the metabolism of labeled pyridoxine in man. Am J Clin Nutr 18:185–196. Kang-Yoon SA, Kirksey A, Giacoia GP, West KD. 1995. Vitamin B6 adequacy in neonatal nutrition: Associations with preterm delivery, type of feeding, and vitamin B-6 supplementation. Am J Clin Nutr 62:932–942. Khera KS. 1975. Teratogenicity study in rats given high doses pyridoxine (vitamin B6) during organogenesis. Experientia 31:469–470.

OCR for page 150
DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline Kirksey A, Roepke JL. 1981. Vitamin B6 nutriture of mothers of three breast-fed neonates with central nervous system disorders. Fed Proc 40:864. Kirksey A, Keaton K, Abernathy RP, Greger JL. 1978. Vitamin B6 nutritional status of a group of female adolescents. Am J Clin Nutr 31:946–954. Kretsch MJ, Sauberlich HE, Newbrun E. 1991. Electroencephalographic changes and periodontal status during short-term vitamin B-6 depletion of young, nonpregnant women. Am J Clin Nutr 53:1266–1274. Kretsch MJ, Sauberlich HE, Skala JH, Johnson HL. 1995. Vitamin B-6 requirement and status assessment: Young women fed a depletion diet followed by a plant-or animal-protein diet with graded amounts of vitamin B-6. Am J Clin Nutr 61:1091–1101. Leklem JE. 1990. Vitamin B-6: A status report. J Nutr 120:1503–1507. Leklem JE. 1991. Vitamin B6. In: Machlin LJ ed. Handbook of Vitamins, 2nd edition. New York: Marcel Dekker. Pp. 341–392. Leklem JE. 1994. Vitamin B6. In: Shils ME, Olson JA, Shike M, eds. Modern Nutrition in Health and Disease. Philadelphia: Lea & Febiger. Pp. 383–394. Leklem JE, Shultz TD. 1983. Increased plasma pyridoxal 5'-phosphate and vitamin B-6 in male adolescents after 4500-meter run. Am J Clin Nutr 38:541–548. Lindberg AS, Leklem JE, Miller LT. 1983. The effect of wheat bran on the bioavailability of vitamin B-6 in young men. J Nutr 113:2578–2586. Linkswiler HM. 1978. Vitamin B6 requirements of men. In: Human Vitamin B6 Requirements: Proceedings of a Workshop. Washington, DC: National Academy of Sciences. Pp. 279–290. Lui A, Lumeng L, Aronoff GR, Li T-K. 1985. Relationship between body store of vitamin B6 and plasma pyridoxal-P clearance: Metabolic balance studies in humans . J Lab Clin Med 106:491–497. Lumeng L, Li TK. 1974. Vitamin B6 metabolism in chronic alcohol abuse. Pyridoxal phosphate levels in plasma and the effects of acetaldehyde on pyridoxal phosphate synthesis and degradation in human erythrocytes. J Clin Invest 53:693–704. Lumeng L, Cleary RE, Li TK. 1974. Effect of oral contraceptives on the plasma concentration of pyridoxal phosphate. Am J Clin Nutr 27:326–333. Lumeng L, Cleary RE, Wagner R, Pao-Lo Y, Li TK. 1976. Adequacy of vitamin B6 supplementation during pregnancy: A prospective study. Am J Clin Nutr 29:1376–1383. Lumeng L, Ryan MP, Li TK. 1978. Validation of the diagnostic value of plasma pyridoxal 5'-phosphate measurements in vitamin B6 nutrition of the rat. J Nutr 108:545–553. Manore MM, Leklem JE. 1988. Effect of carbohydrate and vitamin B6 on fuel substrates during exercise in women. Med Sci Sports Exerc 20:233–241. Manore MN, Leklem JE, Walter MC. 1987. Vitamin B6 metabolism as affected by exercise in trained and untrained women fed diets differing in carbohydrate and vitamin B6 content. Am J Clin Nutr 46:995–1004. Marcus RG. 1975. Suppression of lactation with high doses of pyridoxine. S Afr Med J 49:2155–2156. Merrill AH Jr, Henderson JM, Wang E, McDonald BW, Millikan WJ. 1984. Metabolism of vitamin B-6 by human liver. J Nutr 114:1664–1674. Meydani SN, Ribaya-Mercado JD, Russell RM, Sahyoun N, Morrow FD, Gershoff SN. 1991. Vitamin B-6 deficiency impairs interleukin 2 production and lymphocyte proliferation in elderly adults. Am J Clin Nutr 53:1275–1280.

OCR for page 150
DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline Miller LT, Linkswiler H. 1967. Effect of protein intake on the development of abnormal tryptophan metabolism by men during vitamin B6 depletion. J Nutr 93:53–59. Miller LT, Johnson A, Benson EM, Woodring MJ. 1975. Effect of oral contraceptives and pyridoxine on the metabolism of vitamin B6 and on plasma tryptophan and α-amino nitrogen. Am J Clin Nutr 28:846–853. Miller LT, Leklem JE, Shultz TD. 1985. The effect of dietary protein on the metabolism of vitamin B6 in humans. J Nutr 115:1663–1672. Mitwalli A, Blair G, Oreopoulos DG. 1984. Safety of intermediate doses of pyridoxine. Can Med Assoc J 131:14. Moss AJ, Levy AS, Kim I, Park YK. 1989. Use of Vitamin and Mineral Supplements in the United States: Current Users, Types of Products, and Nutrients. Advance Data, Vital and Health Statistics of the National Center for Health Statistics, No. 174. Hyattsville, MD: National Center for Health Statistics. Mueller JF, Vilter RW. 1950. Pyridoxine deficiency in human beings induced by desoxypyridoxine. J Clin Invest 29:193–201. Nakano H, Gregory JF 3rd. 1997. Pyridoxine and pyridoxine-5'-beta-D-glucoside exert different effects on tissue B-6 vitamins but similar effects of beta-glucosidase activity in rats. J Nutr 125:2751–2762. Pannemans DL, van den Berg H, Westerterp KR. 1994. The influence of protein intake on vitamin B6 metabolism differs in young and elderly humans. J Nutr 124:1207–1214. Parry GJ, Bredesen DE. 1985. Sensory neuropathy with low-dose pyridoxine. Neurology 35:1466–1468. Phillips WE, Mills JH, Charbonneau SM, Tryphonas L, Hatina GV, Zawidzka Z, Bryce FR, Munro IC. 1978. Subacute toxicity of pyridoxine hydrochloride in the beagle dog. Toxicol Appl Pharmacol 44:323–333. Philpot J, Muntoni F, Skellett S, Dubowitz V. 1995. Congenital symmetrical weakness of the upper limbs resembling brachial plexus palsy: A possible sequel of drug toxicity in the first trimester of pregnancy. Neuromuscul Disord 5:67–69. Raica N Jr, Sauberlich HE. 1964. Blood cell transaminase activity in human vitamin B6 deficiency. Am J Clin Nutr 15:67–72. Ribaya-Mercado JD, Russell RM, Sahyoun N, Morrow FD, Gershoff SN. 1991. Vitamin B-6 requirements of elderly men and women. J Nutr 121:1062–1074. Riggs KM, Spiro A, Tucker K, Rush D. 1996. Relations of vitamin B-12, vitamin B-6, folate, and homocysteine to cognitive performance in the Normative Aging Study. Am J Clin Nutr 63:306–314. Rimm EB, Willett WC, Hu FB, Sampson L, Colditz GA, Manson JE, Hennekens C, Stampfer MJ. 1998. Folate and vitamin B6 from diet and supplements in relation to risk of coronary heart disease among women. J Am Med Assoc 279:359– 364. Robinson K, Mayer EL, Miller DP, Green R, van Lente F, Gupta A, Kottke-Marchant K, Savon SR, Selhub J, Nissen SE, Kutner M, Topol EJ, Jacobsen DW. 1995. Hyperhomocysteinemia and low pyridoxal phosphate. Common and independent reversible risk factors for coronary artery disease. Circulation 92:2825– 2830. Rose CS, Gyorgy P, Butler M, Andres R, Norris AH, Shock NW, Tobin J, Brin M, Spiegel H. 1976. Age differences in vitamin B6 status of 617 men. Am J Clin Nutr 29:847–853.

OCR for page 150
DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline Rose DP. 1978. Oral Contraceptives and Vitamin B6. In: Human Vitamin B6 Requirements: Proceedings of a Workshop. Washington, DC: National Academy Press. Pp. 193-201. Sauberlich HE. 1964. Human requirements for vitamin B6. Vitam Horm 22:807– 823. Sauberlich HE, Canham JE, Baker EM, Raica N Jr, Herman YF. 1972. Biochemical assessment of the nutritional status of vitamin B6 in the human. Am J Clin Nutr 25:629-642. Scaglione D, Vecchione A. 1982. Pyridoxine for the suppression of lactation—a clinical trial on 1592 cases. Acta Vitaminol Enzymol 4:207-214. Schaeppi U, Krinke G. 1985. Differential vulnerability of three rapidly conducting somatosensory pathways in the dog with vitamin B6 neuropathy. Agents Actions 16:567-579. Schaumburg HH, Berger A. 1988. Pyridoxine neurotoxicity. In: Clinical and Physiological Applications of Vitamin B6. New York: Alan R. Liss. Pp. 403-414. Schaumburg H, Kaplan J, Windebank A, Vick N, Rasmus S, Pleasure D, Brown MJ. 1983. Sensory neuropathy from pyridoxine abuse. N Engl J Med 309:445-448. Schumacher MF, Williams MA, Lyman RL. 1965. Effect of high intakes of thiamine, riboflavin and pyridoxine on reproduction in rats and vitamin requirements of the offspring. J Nutr 86:343-349. Schuster K, Bailey LB, Mahan CS. 1981. Vitamin B6 status of low-income adolescent and adult pregnant women and the condition of their infants at birth. Am J Clin Nutr 34:1731-1735. Selhub J, Jacques PF, Wilson PWF, Rush D, Rosenberg IH. 1993. Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. J Am Med Assoc 270:2693-2698. Selhub J, Jacques PF, Bostom AG, D’Agostino RB, Wilson PW, Belanger AJ, O’Leary DH, Wolf PA, Schaefer EJ, Rosenberg IH. 1995. Association between plasma homocysteine concentrations and extracranial carotid-artery stenosis. N Engl J Med 332:286-291. Shane B. 1978. Vitamin B6 and blood. In: Human Vitamin B6 Requirements: Proceedings of a Workshop. Washington, DC: National Academy Press. Pp. 111-128. Shane B, Contractor SF. 1975. Assessment of vitamin B6 status. Studies on pregnant women and oral contraceptive agent users. Am J Clin Nutr 28:739-747. Shane B, Contractor SF. 1980. Vitamin B6 status and metabolism in pregnancy. In: Tryfiates GP, ed. Vitamin B6 Metabolism and Role in Growth. Westport, CT: Food & Nutrition Press. Pp. 137-171. Sharma SK, Dakshinamurti K. 1992. Seizure activity in pyridoxine-deficient adult rats. Epilepsia 33:235-247. Sharma SK, Bolster B, Dakshinamurti K. 1994. Picrotoxin and pentylene tetrazole induced seizure activity in pyridoxine-deficient rats. J Neurol Sci 121:1-9. Shultz TD, Leklem JE. 1981. Urinary 4-pyridoxic acid, urinary vitamin B6, and plasma pyridoxal phosphate as measures of vitamin B6 status and dietary intake in adults. In: Leklem JE, Reynolds RD, eds. Methods in Vitamin B6 Nutrition. New York: Plenum Press. Pp. 389-392. Snell EE. 1958. Some aspects of the metabolism of vitamin B6. In: Fourth International Congress of Biochemistry-Vitamin Metabolism, Vol. 11. New York: Pergamon. Pp. 250-265. Snyderman SE, Holt LE, Carretero R, Jacobs K. 1953. Pyridoxine deficiency in the human infant. Am J Clin Nutr 1:200.

OCR for page 150
DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline Stephens MC, Havlicek V, Dakshinamurti K. 1971. Pyridoxine deficiency and development of the central nervous system in the rat. J Neurochem 18:2407–2416. Subbarao K, Kakkar W. 1979. Thrombin induced surface changes of human platelets. Biochem Biophys Res Commun 88:470–476. Tarr JB, Tamura T, Stokstad EL. 1981. Availability of vitamin B6 and pantothenate in an average American diet in man. Am J Clin Nutr 34:1328–1337. Tolis G, Laliberte R, Guyda H, Naftolin F. 1977. Ineffectiveness of pyridoxine (B6) to alter secretion of growth hormone and prolactin and absence of therapeutic effects on galactorrhea-amenorrhea syndromes. J Clin Endocrinol Metab 44:1197–1199. Ubbink JB, Vermaak WJ, Delport R, van der Merwe A, Becker PJ, Potgieter H. 1995. Effective homocysteine metabolism may protect South African blacks against coronary heart disease. Am J Clin Nutr 62:802–808. Ubbink JB, van der Merwe A, Delport R, Allen RH, Stabler SP, Riezler R, Vermaak WJ. 1996. The effect of a subnormal vitamin B6 status on homocysteine metabolism. J Clin Invest 98:177–184. Unna K, Antopol W. 1940. Toxicity of vitamin B6. Proc Soc Exp Biol Med 43:116–118. van der Beek EJ, van Dokkum W, Wedel M, Schrijver J, van den Berg H. 1994. Thiamin, riboflavin and vitamin B6: Impact of restricted intake on physical performance in man. J Am Coll Nutr 13:629–640. Weinstein BB, Wohl Z, Mitchell GJ, Sustendal GF. 1944. Oral administration of pyridoxine hydrochloride in the treatment of nausea and vomiting of pregnancy. Am J Obstet Gynecol 47:389–394. Weir MR, Keniston RC, Enriquez JI Sr, McNamee GA. 1991. Depression of vitamin B6 levels due to dopamine. Vet Hum Toxicol 33:118–121. West KD, Kirksey A. 1976. Influence of vitamin B6 intake on the content of the vitamin in human milk. Am J Clin Nutr 29:961–969. Willis RS, Winn WW, Morris AT, Newsome AA, Massey WE. 1942. Clinical observations in treatment of nausea and vomiting in pregnancy with vitamin B1 and B6. A preliminary report. Am J Obstet Gynecol 44:265–271. Wozenski JR, Leklem JE, Miller LT. 1980. The metabolism of small doses of vitamin B6 in men. J Nutr 110:275–285. Yess N, Price JM, Brown RR, Swan PB, Linkswiler H. 1964. Vitamin B6 depletion in man: Urinary excretion of tryptophan metabolites. J Nutr 84:229–236.