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Biomedical subjects

D A Bender

Publications and source records attributed to D A Bender.

At least 37 records · Page 2Linked to original sources
PubMed1989

Vitamin B6 requirements and recommendations.

The principal metabolic function of vitamin B6 is in amino acid metabolism, although the greater part of the body's vitamin B6 is in muscle, associated with glycogen phosphorylase, and the vitamin also has an important role in the actions of steroid hormones. It is usual to calculate vitamin B6 requirements relative to protein intake. An adequate intake to meet the requirements of virtually the whole population is generally considered to be 15 micrograms/g dietary protein. This is the basis of RDAs in most countries, although differences of interpretation and application of the experimental data result in widely differing recommendations from different authorities. Current RDAs range between 1.5 and 2.2 mg/d. A minimum safe intake, below which an individual would have a high probability of deficiency, is 11 micrograms/g dietary protein. Higher intakes are required in pregnancy and lactation (although there are problems in determining the requirement of the infant), and possibly also in the elderly. Average intakes of vitamin B6 in developed countries meet the target of 15 micrograms/g dietary protein, although there is biochemical evidence of inadequate vitamin B6 nutritional status in 10-25 per cent of the population. It is not know whether this has any clinical significance; it is unlikely that normal patterns of food intake would permit a significantly greater average intake of the vitamins without fortification or the use of supplements. There is little evidence that pharmacological doses of vitamin B6 have any beneficial effect. Neurological damage has been reported at extremely high intakes (in excess of 500 mg/d), and even more modest doses (50-100 mg/d) cannot be regarded as being without hazard.

Adolescent↗
PubMed1988

Utilization of tryptophan, nicotinamide and nicotinic acid as precursors for nicotinamide nucleotide synthesis in isolated rat liver cells.

1. Incubation of isolated rat hepatocytes with nicotinamide or nicotinic acid showed that while both vitamers were taken up from the incubation medium, neither was utilized to any significant extent as a precursor of the nicotinamide nucleotide coenzymes, NAD and NADP, and neither was capable of preventing the loss of nucleotides that occurs on incubating the cells. 2. Incubation of hepatocytes with tryptophan showed that de novo synthesis from tryptophan permitted replacement of the nucleotides lost during incubation; at high concentrations of tryptophan there was an increase above the initial intracellular concentration of NAD(P). Incubation of hepatocytes with tryptophan also resulted in the formation and release from the cells of a considerable amount of niacin, as well as the two principal metabolities of NAD(P), N1-methyl nicotinamide and methyl pyridone carboxamide. 3. It is suggested that, in the liver, performed niacin is not utilized for nucleotide synthesis, and indeed the function of the liver appears to be synthesis of niacin from tryptophan, and its release for use by extrahepatic tissues that lack the pathway for de novo synthesis of nicotinamide nucleotides from tryptophan.

Animals↗
PubMed1986

Increased uterine uptake and nuclear retention of [3H]oestradiol through the oestrous cycle and enhanced end-organ sensitivity to oestrogen stimulation in vitamin B6 deficient rats.

Vitamin B6 deficient female rats showed a significantly earlier, greater and more prolonged uptake of a tracer dose of [3H]oestradiol into the uterus, with increased nuclear accumulation, compared with vitamin B6 supplemented animals. This was most marked at oestrus, with little difference at anoestrus. The responses to low doses of ethynyl-oestradiol were greater in ovariectomized deficient animals than in those receiving the supplemented diet, with an increased uterotrophic response and greater induction of peroxidase. In the deficient animals there was virtually complete suppression of LH secretion at doses of ethynyl-oestradiol that had no effect in controls. At high doses of ethynyl-oestradiol there was no difference between the two groups of animals. The results suggest that increased uterine uptake and accumulation of [3H]oestradiol in vitamin B6 deficiency is associated with enhanced end-organ responsiveness to sub-maximal oestrogen stimulation, and that pyridoxal phosphate may have a coenzyme role in oestrogen action.

Animals↗
PubMed1986

The metabolism of high intakes of tryptophan, nicotinamide and nicotinic acid in the rat.

1. The metabolic fate of high dietary intakes of nicotinamide, nicotinic acid and tryptophan, and of acute doses of nicotinamide and nicotinic acid, has been studied in the rat. A new high-pressure liquid chromatography method for measurement of the principal urinary metabolites of niacin is described. 2. Administration to rats of a single oral dose of nicotinamide or nicotinic acid (up to 100 mg/kg body-weight), or maintenance for 3 weeks on diets providing 150 mg nicotinamide or nicotinic acid/kg diet, resulted in only a small increase in the liver content of nicotinamide nucleotide coenzymes (NAD and NADP). The quantitative metabolism of nicotinamide and nicotinic acid differed, suggesting that intestinal bacterial deamidation is not the major fate of nicotinamide. 3. A high dietary intake of tryptophan (5.9 g/kg diet) led to a considerable increase in liver NAD(P) and also in urinary excretion of niacin metabolites. The results suggest that, as indicated by enzyme kinetic studies (Bender et al. 1982), the utilization of nicotinamide and nicotinic acid for nucleotide synthesis is limited, while there is little or no limitation of NAD(P) synthesis from the tryptophan metabolite quinolinic acid.

Animals↗
PubMed1985

Leucine and tryptophan metabolism in rats.

The rate of tryptophan metabolism in isolated liver cells from animals fed on a high-leucine diet was greater than for cells from control animals. Leucine inhibited tryptophan metabolism and tryptophan uptake in isolated liver cells, probably by competing for membrane transport. Leucine had no effect on tryptophan 2,3-dioxygenase in vitro. 4-Methyl-2-oxovalerate increased tryptophan oxidation in incubations containing albumin, by displacing bound tryptophan and increasing the availability of the amino acid to the cell. The results suggest that, under extreme conditions, when the availability of tryptophan is low, leucine may be pellagragenic.

Animals↗
PubMed1985

Lethal familial pellagra-like skin lesion associated with neurologic and developmental impairment and the development of cataracts.

A new hereditary defect of tryptophan metabolism is described in a Sudanese family with a high degree of consanguinity. It has an autosomal recessive pattern of inheritance. The condition manifests as a pellagra-like skin rash within 8 weeks after birth, with signs of cerebellar ataxia and developmental retardation. Cataracts develop early, and to date none of the ten affected children has survived beyond 2 years of age. Biochemically, the condition is characterized by an apparent impairment of the ability to synthesize quinolinic acid and nicotinamide nucleotides from tryptophan, which might be due to abnormally high activity of the enzyme picolinate carboxylase.

Amino Acid Metabolism, Inborn Errors↗
PubMed1984

Increased target tissue uptake of, and sensitivity to, testosterone in the vitamin B6 deficient rat.

Six-week old male rats were maintained for 4 weeks on a vitamin B6-free diet to cause a moderately severe degree of vitamin B6 depletion. This led to a significant reduction in the circulating concentration of testosterone in plasma (control = 8.36 +/- 1.68, deficient = 2.13 +/- 0.54 nmol/l), but had no effect on circulating concentrations of luteinizing hormone, or, in intact males, on the weight of the prostate relative to body weight. In both intact and 24-h castrated animals vitamin B6 deficiency resulted in a significant increase in the uptake of [3H]testosterone into the prostate, and both increased and prolonged the specific nuclear retention of the steroid, as assessed by the ratio of radioactivity in the nuclear pellet: the high speed supernatant fraction. The results suggest that vitamin B6 has a function in the action of testosterone (and other steroid hormones), possibly in the recycling of receptors from the nucleus back into the cytosol after initial translocation. Vitamin B6 deficient animals have either a reduced rate of synthesis of testosterone or an increased rate of metabolic clearance compared with vitamin B6 supplemented controls, and this appears to be associated with enhanced target organ response to the hormone.

Animals↗
PubMed1984

Inhibition of tryptophan metabolism by oestrogens in the rat: a factor in the aetiology of pellagra.

The effect of the administration of oestrone sulphate on tryptophan metabolism has been assessed in rats in order to determine whether and to what extent inhibition of tryptophan metabolism by oestrogens may be a factor in the aetiology of pellagra, and might explain the reported twofold excess of females over males in many outbreaks of pellagra. Feeding ovariectomized rats for 1 week on a diet containing 15 mg oestrone sulphate/kg led to significant inhibition of kynurenine hydroxylase (EC 1.14.13.9), kynureninase (EC 3.7.1.3) and 3-hydroxyanthranilate oxidase (EC 1.13.11.6). There was also a significant increase in plasma tryptophan, suggesting decreased activity of tryptophan oxygenase (EC 1.13.11.11). This inhibition of tryptophan metabolism will result in a considerable reduction in the synthesis of the nicotinamide nucleotide coenzymes (NAD and NADP) from tryptophan. When ovariectomized rats were maintained for 4 weeks on a diet providing no preformed niacin and only a marginally adequate amount of tryptophan (1030 mg/kg), the addition of sulphate to the diet led to a significant reduction in the liver content of nicotinamide nucleotides and the urinary excretion of the end-product of NAD metabolism, N1-methyl nicotinamide. It is suggested that when the diet is only marginally adequate in tryptophan and niacin, inhibition of tryptophan metabolism by endogenous or administered oestrogens may be an additional factor in the development of pellagra.

Animals↗
PubMed1984

High doses of vitamin B6 in the rat are associated with inhibition of hepatic tryptophan metabolism and increased uptake of tryptophan into the brain.

Acute administration of vitamin B6 to rats (10 mg/kg body weight) led to reduced urinary excretion of N1-methyl nicotinamide and methyl pyridone carboxamide, indicating inhibition of the oxidative metabolism of tryptophan. There was a considerable reduction in the production of 14CO2 from [ring-2-14C]tryptophan, and a significant inhibition of hepatic tryptophan oxygenase when measured in liver homogenates, together with an increase in the concentration of tryptophan in plasma. There was an increase in both the concentration of tryptophan in the brain and the uptake into the brain of peripherally administered [3H]tryptophan, accompanied by a small increase in the rate of synthesis of 5-hydroxytryptamine in the brain. It is suggested that this increase in the uptake of tryptophan into the brain following a relatively large dose of vitamin B6 may explain the beneficial action of the vitamin in some cases of depressive illness.

Animals↗
PubMed1983

The role of catabolism in controlling tissue concentrations of nicotinamide nucleotide coenzymes.

A previous report from this laboratory (Bender, D.A., Magboul, B.I. and Wynick, D. (1982) Brit. J. Nutr. 48, 119-127) suggested that the hydrolysis of the nicotinamide nucleotides NAD and NADP may be an important factor in controlling the tissue content of these coenzymes. Further studies presented here support this suggestion. Both nuclear poly(ADPribose) synthetase and microsomal NAD glycohydrolase showed activity towards both NAD+ and NADP+, and the two nucleotides were mutually competitive. The reduced nucleotides, NADH and NADPH, were not substrates for either enzyme. In rats that were maintained for 24 h under conditions of hypoxia (O2/N2, 1:9) there was an increase in the proportion of nicotinamide nucleotides present in the liver in the reduced form, and an increase in the total concentration of nucleotides in the liver. In rats that were maintained for 24 h under conditions of hyperoxia (O2/N2, 7:3) there was no change in either the proportion of nicotinamide nucleotides in the liver present in the reduced form or in the total tissue control of the nucleotides. There was an increase in the urinary excretion of kynurenine suggesting an increase in the oxidative metabolism of tryptophan.

Aerobiosis↗
PubMed1983

The effects of oestrogen administration on tryptophan metabolism in rats and in menopausal women receiving hormone replacement therapy.

The effects of the administration of oestrogens on the activity of hepatic tryptophan oxygenase have been assessed both directly (by measurement of enzyme activity in vitro) and indirectly (by measurement of urinary excretion of tryptophan metabolites) in rats, and indirectly in menopausal women receiving hormone replacement therapy. Intraperitoneal administration of 500 micrograms of oestradiol or ethinyl oestradiol/kg body wt had no effect on the activity of tryptophan oxygenase in homogenates of liver from mature (13-week-old) female rats. Both adrenalectomy and ovariectomy led to a reduction in the activity of tryptophan oxygenase in homogenates of liver from mature rats; again there was no effect of giving 500 micrograms of oestradiol/kg body wt by intraperitoneal injection. Intraperitoneal administration of 210 micrograms of oestrone sulphate/kg body wt for 1 or 2 days before killing, or its incorporation in the diet for up to 8 weeks at an equivalent dose rate, had no effect on the activity of tryptophan oxygenase in homogenates of liver from ovariectomized 6-14-week-old female rats. Intraperitoneal administration of 500 micrograms oestradiol/kg body wt to intact mature female rats together with 500 mg tryptophan/kg body wt caused a reduction in the urinary excretion of xanthurenic and kynurenic acids, kynurenine and N1-methyl nicotinamide. When peri- and post-menopausal women were treated with ethinyl oestradiol (20 micrograms/day) or piperazine oestrone sulphate (3 mg/day) for 3 months, there was an increase in the concn of tryptophan in plasma, with no change in the urinary excretion of xanthurenic and kynurenic acids and kynurenine. This study provides no evidence for the induction of tryptophan oxygenase by oestrogens in rats or human beings.

Adrenalectomy↗
PubMed1983

Effects of vitamin B6 nutritional status on the uptake of [3H]-oestradiol into the uterus, liver and hypothalamus of the rat.

Rats were depleted of vitamin B6 by treatment with isoniazid, and then maintained on diets providing: no vitamin B6, an adequate amount (1.2 mg/kg diet) or a very large amount (120 mg/kg) for 5 weeks. The uptake of a tracer dose of [3H]-oestradiol into the nuclei of liver and uterus was significantly greater in deficient animals than in those receiving an adequate or greater than adequate amount of the vitamin. Similarly the accumulation of oestradiol in the region of the brain corresponding to the hypothalamus, pre-optic area and septum (the major oestradiol-sensitive regions of the central nervous system) was higher in deficient animals than in other groups. There were significant inverse correlations between the uptake of oestradiol into target tissues and vitamin B6 nutritional status as determined by the concentrations of pyridoxal phosphate in plasma and liver. Uteri from deficient animals were significantly smaller than those from animals receiving an adequate or greater amount of vitamin B6, and the induction of uterine peroxidase by oestradiol was impaired. It therefore seems likely that despite the greater net accumulation of steroid in target tissues, vitamin B6 deficiency impairs biological responsiveness to oestrogens. It is suggested that this may be due to a failure of the recycling of oestradiol receptors from the nucleus.

Animals↗