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D A Bender

Publications and source records attributed to D A Bender.

At least 55 records · Page 3Linked to original sources
PubMed1983

Effects of a dietary excess of leucine on the metabolism of tryptophan in the rat: a mechanism for the pellagragenic action of leucine.

In order to investigate the mechanism of the pellagragenic action of excess dietary leucine, rats were fed on diets providing a minimally-adequate amount of tryptophan, with no preformed niacin, with and without the addition of 15 g leucine/kg diet. This amount of leucine in the diet has been demonstrated previously to lead to depletion of blood and liver nicotinamide nucleotides. The metabolism of tryptophan was assessed by measurement of the production of 14CO2 after the administration of [methylene-14C]tryptophan to estimate the activity of kynureninase (L-kynurenine hydrolase, EC 3.7.1.3) and [benzene ring U-14C]tryptophan to estimate the activity of picolinate carboxylase (aminocarboxymuconate semialdehyde decarboxylase, EC 4.1.1.45). A dietary excess of leucine led to inhibition of kynureninase and increased the activity of picolinate carboxylase. Both of these effects would result in a reduction in the rate of metabolism of acroleylaminofumarate (aminocarboxymuconate semialdehyde) to quinolinic acid and hence to nicotinamide nucleotides. These two effects provide an explanation for the pellagragenic effect of a dietary excess of leucine in animals that are wholly or partly reliant on endogenous synthesis from tryptophan to meet their requirements for nicotinamide nucleotides, and presumably also explain the pellagragenic effect of a dietary excess of leucine in man.

Animals↗
PubMed1983

Cushing's syndrome and depression--a prospective study of 26 patients.

Of 26 patients with active Cushing's syndrome assessed before and at three and 12 months after treatment, 21 had pituitary-dependent disease. Median urinary free cortisol values (per 24 hours) were 680, 180 and 200 nmol at zero, three and 12 months (normal less than 270 nmol), with significant improvement (P less than 0.001) at three and 12 months. Depression on the Hamilton rating scale was significantly less at three months (P less than 0.01) and at 12 months (P less than 0.001). We have already demonstrated that some patients with Cushing's syndrome have PSE diagnoses of depression and are more depressed than patients with other pituitary tumours. This is the firmest evidence to date that when Cushing's syndrome occurs it commonly causes depressive illness.

Adolescent↗
PubMed1982

The preferred route of kynurenine metabolism in the rat.

It has been suggested (Ueda, T., Otsuka, H. and Goda, K. (1978) J. Biochem. 84, 687-696) that direct cleavage of kynurenine, catalysed by kynureninase, followed by microsomal hydroxylation of the resultant anthranilic acid, may provide an alternative to the established pathway of kynurenine metabolism that involves direct hydroxylation followed by cleavage to 3-hydroxyanthranilic acid. To test this suggestion, anthranilic acid was administered to rats; there was no increase in either the concentration of nicotinamide nucleotides in the liver or the urinary excretion of N1-methyl nicotinamide. However, injection of either kynurenine or 3-hydroxyanthranilic acid did increase the concentration of nicotinamide nucleotides in the liver. The kinetics of kynurenine hydroxylase (Km = 1.8 +/- 0.6.10(-5) mol/l) and kynureninase (Km = 2.5 +/- 0.8.10(-4) mol/l, liver steady-state kynurenine = 4.9 +/- 0.9 mumol/kg) are such that the preferred route of kynurenine metabolism is probably by way of hydroxylation rather than cleavage.

Animals↗
PubMed1982

Effects of oestrogen administration on vitamin B6 and tryptophan metabolism in the rat.

1. In order to assess the effects of oestrogens on the metabolism of tryptophan and vitamin B6, ovariectomized rats have been maintained on diets providing known amounts of tryptophan, nicotinamide and vitamin B6. They received oestrone sulphate, 210 micrograms/kg body-wt per d, either incorporated in the diet for 8 weeks, or by daily intraperitoneal injection for periods of 1-3 d. 2. Oestrone sulphate administration caused a slight reduction in the concentration of pyridoxal phosphate in plasma. It had no effect on the concentration of pyridoxal phosphate in liver or kidney, the urinary excretion of 4-pyridoxic acid, the activation of erythrocyte aspartate aminotransferase (L-aspartate:2-oxo-glutarate aminotransferase, EC 2. 6. 1. 1) by incubation with added pyridoxal phosphate, or the activity of pyridoxal oxidase (aldehyde:oxygen oxido-reductase, EC 1.2.3.1) in the liver. 3. Oestrone sulphate administration caused an increase in the urinary excretion of kynurenine and a reduction in the activity of liver kynureninase (L-kynurenine hydrolase, EC 3.7.1.3). It had no effect on the urinary excretion of N1-methyl nicotinamide or the concentrations of nicotinamide nucleotides in blood, liver or kidney. 4. There was a considerable excess of the apoenzyme of kynureninase in the liver. Incubation of liver homogenates with added pyridoxal phosphate led to a 4- to 5-fold increase in activity. 5. We conclude that there is no evidence of any significant effect of oestrogens on vitamin B6. It is suggested that abnormalities of tryptophan metabolism in women receiving oestrogens, which have been widely attributed to drug-induced vitamin B6 depletion, can be accounted for by inhibition of kynureninase by oestrogen metabolites.

Animals↗
PubMed1981

Inhibition of kynureninase (L-kynurenine hydrolase, EC 3 . 7. 1 . 3) by oestrone sulphate: an alternative explanation for abnormal results of tryptophan load tests in women receiving oestrogenic steroids.

1. A partial purification of kynureninase (L-kynurenine hydrolase, EC 3 . 7. 1 . 3) from rat liver and a total resolution of the apoenzyme have been achieved. The hypothesis that conjugates of oestrogenic steroids compete with pyridoxal phosphate for the cofactor binding site of the enzyme, and so disturb tryptophan metabolism, leading to apparent vitamin B6 deficiency, has been tested. 2. Kynureninase from rat liver was partially purified, and the cofactor-free apoenzyme was prepared. Oestrone sulphate inhibited the enzyme uncompetitively with respect to pyridoxal phosphate, and competitively with respect to kynurenine, with a mean (+/- SE) inhibitor constant (Ki) of 82 +/- 6 microM. 3. The addition of a saturating concentration of pyridoxal phosphate to unfractionated liver homogenates led to an approximately fivefold increase in kynureninase activity, indicating the presence of a relatively large amount of apo-kynureninase in the tissue. 4. It is suggested that the abnormal results of tryptophan load tests in women receiving oestrogens are the result of inhibition of kynureninase by oestrogen conjugates, and that there is no evidence for oestrogen-induced vitamin B deficiency in such cases.

Animals↗
PubMed1980

Cushing's syndrome, tryptophan and depression.

Fifteen patients with active Cushing's syndrome have been compared with 15 other patients who had been treated successfully for Cushing's syndrome and with 13 patients with other pituitary tumours. Depression was the main psychiatric diagnosis made by the CATEGO programme after Present State Examinations. Patients with active Cushing's syndrome were significantly more depressed (Hamilton Rating Scores), than were the other patients. Compared with the control patients, those with active Cushing's syndrome had slightly lower plasma concentrations of total tryptophan, though the concentrations of freely diffusible tryptophan were not significantly changed.

Adolescent↗
PubMed1979

Niacin depletion in Parkinsonian patients treated with L-dopa, benserazide and carbidopa.

1. Benserazide and carbidopa, decarboxylase inhibitors used in the treatment of Parkinson's disease, have been shown to inhibit the enzyme kynurenine hydrolase in rat and mouse liver. This results in reduced synthesis of nicotinamide coenzymes from tryptophan, and hence an increased reliance on dietary niacin. 2. Pellagra might be expected as a result of this inhibition of endogenous synthesis of nicotinamide nucleotides, but has not been reported in patients treated with either drug. 3. The urinary excretion of N1-methyl-nicotinamide, a product of nicotinamide nucleotide metabolism, is considerably reduced in patients treated with dopa alone or in combination with an inhibitor of peripheral dopa decarboxylase, to as low as 40% of the control value. This means that many of these patients could be classified as 'at risk' of niacin deficiency, even if not frankly deficient. 4. Patients treated with dopa plus a decarboxylase inhibitor, but not those treated with dopa alone, also show a reduced excretion of xanthurenic acid, and an increased excretion of kynurenine, as would be expected after inhibition of the kynurenine pathway, and possibly indicative of marginal vitamin B6 deficiency.

Adolescent↗