Avitaminosis and congenital malformations.
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Biomedical subjects
Publications and source records attributed to T K Basu.
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Base-line values for the excretion of urea N, amine N, creatinine, uric acid and cysteine were measured in three consecutive 24-h urine collections from 16 healthy volunteers. The subjects then took 1 g ascorbic acid three times a day after meals for 7 days. Twenty-four hour urine samples were collected on the 1st, 3rd, 5th and 7th days of the study. Where possible, a further 24-h sample was collected a minimum of 10 d after the end of the study. Administration of 3 g/d of ascorbic acid had no effect on urine volume, pH or the excretion of urea, amino N or creatinine. It caused a transient increase in uric acid excretion but an immediate and sustained increase in the excretion of cysteine. This study provides no evidence for an effect of high doses of ascorbic acid on urinary stone formation but does suggest competition for important co-factors in the metabolism of drugs.
A study was undertaken to investigate the interactions between aspirin and ascorbic acid in guinea pigs. Animals received by gastric intubation either a single dose of radiolabelled ascorbic acid alone or ascorbic acid with aspirin and the exhalation of CO2 was monitored for 400 min following administration. Animals receiving the vitamin only reached plasma peak levels within 90 min following administration while coadministration of the vitamin with aspirin, not only resulted in lower plasma peak levels, but also delayed their attainment until after 160 min. The bioavailability of ascorbic acid during the first 400 min was reduced by half following simultaneous administration of aspirin. The initial rate of exhalation of CO2 was decreased by 70% following coadministration of aspirin. These observations indicate that aspirin impairs the gastrointestinal absorption of ascorbic acid in guinea pigs, possibly by interfering with its active transport.
Reports of the beneficial effects of large doses of ascorbic acid have stressed its water solubility and non-toxic properties. In this study male guinea pigs, dosed with 150 mg twice daily, ascorbic acid, demonstrated no differences in effect on liver weight, body weight or hepatic total protein when compared with controls. The activities of NADPH-dependent cytochrome c reductase, N-demethylase (Type I) and O-de-ethylase enzymes (Type II) remained unaffected, but the activity of the Type I hydroxylating enzyme, biphenyl-4-hydroxylase, and the amounts of cytochromes P-450 and b5 were significantly reduced. Total microsomal haem proteins were reduced and mirrored the effects in cytochromes P-450 and b5. The rate-limiting enzyme in haem synthesis, delta-amino-laevulinic acid synthetase, rose in the ascorbic acid group and this was associated with a fall in activity of the haem degrading enzyme, microsomal haem oxygenase. Thus, large amounts of ascorbic acid have similar effects to those found in scorbutic animals and appear to interfere with the construction of the cytochrome P-450 molecule.
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Serum vitamin A and retinol-binding protein (RBP) concentrations were measured in patients comprising 53 myeloma and 28 epithelial cell cancer cases. Vitamin A levels in these patients were found to be significantly lower than those in the 30 healthy subjects, the effect being more marked in the patients with cancer of epithelial origin. The serum concentrations of retinol-binding protein (RBP) fell in parallel with vitamin A in the epithelial cancer patients, while the RBP concentrations remained unaffected in the patients with myeloma, suggesting that the underlying factor for resulting low vitamin A levels may be different in these two groups of patients.
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The effect of soluble aspirin on the availability of vitamin C has been studied in guinea-pigs and human subjects. In the human study, the concentrations of vitamin C in plasma, leucocytes and urine were found to be markedly elevated at various intervals following administration of a single oral dose of 500 mg of the vitamin. The vitamin C-associated increases, however, appeared to be blocked when the vitamin was given simultaneously with aspirin (900 mg). Similar findings were observed in guinea-pigs, where in addition faecal excretion of vitamin C was found to be significantly increased when the vitamin was administered together with aspirin. These results suggest that aspirin may impede gastrointestinal absorption of vitamin C. This hypothesis has been strengthened with in vitro studies using everted gut sac preparations where both the serosal/mucosal concentration gradient and the uptake of vitamin C per unit weight of intestine were markedly lowered by acetyl-salicylate. Such an interaction is relevant to the population where vitamin C intake is borderline.
Intragastric administration of ethanol to male rats given at 6 gm/kg body weight, daily for two weeks, produced no significant change in the body or liver weights. Hepatic total lipid increased but this was no more than a trend. Treatment with ethanol, however, resulted in a marked decrease in transketolase activity (TK) of the haemolysed whole blood, associated with a pronounced rise in the stimulating effect of thiamin pyrophosphate on this enzyme (TPP effect). These changes mediated by ethanol were counteracted by hymochromone.
The administration of large doses of corticosterone to normal adult male rats resulted in a rapid loss of vitamin A from the plasma, liver, adrenals and thymus. Of the organs studied, the thymus appeared to be the most sensitive to treatment. The steroid-mediated depression of plasma and tissue contents of vitamin A was reversed when animals were treated with corticosterone in combination with vitamin A.
In a short trial, 24 patients with Paget's disease of the bone were treated for 2 weeks with either ascorbic acid and calcitonin in combination, or with calcitonin alone. Pain relief was then assessed subjectively by the patients and classified as nil, some, or a marked reduction in pain. There were 11 patients in the group on combined therapy and 73% of them experienced pain relief, compared with 85% of the 13 patients in the group on calcitonin alone. In the patients who experienced pain relief, however, 62% of those on the ascorbic acid and calcitonin combination claimed a marked relief of pain compared with only 36% of the patients who responded to calcitonin alone. These results indicate that when calcitonin and ascorbic acid are used in combination they may provide an increase in the extent of pain relief, but do not increase the total proportion of patients actually obtaining relief. Urinary hydroxyproline excretion was reduced in the calcitonin treated group, but there was little change in the patients on the combined therapy.
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Serum vitamin A concentration were measured in 26 newly diagnosed lung-cancer patients and found to be significantly lower than those of patients of similar age with either non-malignant lung or non-lung diseases. The levels of vitamin A in the lung-cancer patients, but not in the controls, were significantly correlated with serum concentrations of retinol-binding protein (RBP) and zinc. It is suggested that low levels of zinc might reduce the synthesis of RBP and thus reduce the mobilization of vitamin A from the liver.
In normal weanling male rats, the intraperitoneal administration of zinc sulphate (ZnSO4) resulted in a decreased hepatic and an increased plasa concentration of vitamin A after 2 h. In an in vitro study, the vitamin A concentrations of liver homogenates were markedly increased when homogenized livers were treated with ZnSO4, ZnSO4, however, did not show any effect on plasma and liver concentrations of vitamin E. These results indicate that zinc may be specifically involved in mobilizing vitamin A from liver to the circulation of normal animals within a short period. The trace element, therefore, could be used only to treat cases of depressed vitamin A in plasma but also to treat hepatic toxicity from hypervitaminosis A.
The sensitivity of the hydroxyproline (OHP)/creatinine (Cr) index and the free urinary alkaline ribonuclease activity as indices of nutritional status have been compared using rats as an experimental model. The results have revealed that the OHP/Cr index is a better biochemical parameter than the urinary alkaline ribonuclease activity for indicating a subclinical degree of malnutrition.
The effect of 5-fluorouracil on the thiamin status of normal female adult rats has been investigated. Pre-treatment of the animals with the cytotoxic drug daily for 3 successive days resulted in a significant decrease in hepatic concentrations of thiamin concomitant with a decrease in thiamin-dependent transketolase enzyme activity and an increase in thiamin-pyrophosphate-(TPP-)stimulating effect in whole blood when compared with those of pair-fed control animals. The TPP effect of transketolase enzyme activity was also increased by 5-fluorouracil in vitro. Furthermore, the treatment with 5-fluorouracil resulted in decreased liver and spleen concentrations without affecting the urinary excretory levels of thiamin in animals supplemented with large doses of the vitamin. Giving a dose comparable to a human therapeutic dose caused a similar increase in the TPP effect. These results indicate that treatment with 5-fluorouracil may be associated with thiamin deficiency by increasing either the utilization or the breakdown of thiamin.
Animal studies have shown. a) an association between vitamin A and cancers of epithelial origin, and b) that vitamin A and its analogues delay tumour appearance, retard tumour growth and regress tumours induced by carcinogenic polycyclic aromatic hydrocarbons. Human epidemiological and biochemical studies suggest that cancers of epithelial origin may be associated with vitamin A deficiency. Vitamin A and its analogues may have a prophylactic and a therapeutic role in cancers of epithelial origin.
Previous work in this laboratory has thrown some light on the possible mechanism involved in the anti-tumour activity of ascorbic acid (AA). In order to elucidate this mechanism further, the present studies, involving the effect of AA on protein and RNA synthesis, were carried out. The results obtained in this investigation may support the hypothesis previously put forward for the action of AA on cell proliferation.