The effects of ageing on aminopyrine and caffeine breath tests in the rat.

The influence of ageing on demethylation of 14C-aminopyrine (AP) and 14C-caffeine (Caf) in Wistar littermate rats was studied serially using the 14CO2-breath test. In both sexes, the elimination half-life (t1/2) of 14C-AP fell from a mean of approximately 75 min when weaned at 17 days to 45 min at maturity (49 days); thereafter t1/2 became prolonged, being most prolonged (82 min) in elderly male rats (210 days). Similarly, t1/2 of 14C-Caf was also prolonged with ageing. These studies using in vivo and longitudinal techniques indicate the importance of ageing on hepatic demethylation.

Ascorbic acid and cortisol metabolism in hypovitaminosis C guineapigs.

The relationship between the metabolic changes in tissue ascorbic acid (AA) and the release of 11-hydroxy corticosteroids (cortisol) into the blood of male and female guineapigs fed on vitamin C-deficient diet, has been investigated. The animals received the diet for 30 and 36 days (males and females respectively) during which tissue AA and Corticol concentrations were analysed at six-day intervals. Bodyweight and adrenal weights were also recorded. When guineapigs are deprived of vitamin C in their diet, tissue cortisol and ascorbic acid concentrations undergo concurrent metabolic changes. There is a close association between the metabolic changes in adrenal cortisol secretion and ascorbic acid release into the plasma as shown by the regression and correlation values. Adrenal ascorbic acid concentration falls as cortisol secretion into the plasma increases. These results indicate that adrenal ascorbic acid operates a modulating role over the production of adrenal steroids during stress in guineapigs.

How vitamin C, clofibrate and diosgenin control cholesterol metabolism in male guinea-pigs.

Following daily administration of cholesterol-enriched scorbutogenic diet to male guinea-pigs for 24 days, elevation of tissue cholesterol level occurred with concurrent pronounced depletion of tissue ascorbic acid. When these hypercholesterolemic guinea-pigs received clofibrate or diosgenin with or without daily supplementary vitamin C for 10 days, alterations in the bodyweight, plasma and hepatic ascorbic acid and clofibrate and diosgenin separately caused reduction in bodyweight and also in tissue ascorbic acid and cholesterol levels. In contrast, bodyweight and tissue ascorbic acid concentrations were increased by vitamin C alone or in combination with clofibrate or diosgenin. The cholesterol lowering actions of clofibrate and diosgenin were enhanced by daily supplementary vitamin C in hypercholesterolemic guinea-pigs. It is concluded that vitamin C plays an important role in the control of cholesterol metabolism in hypercholesterolemic guinea-pigs receiving clofibrate or diosgenin.

Ascorbic acid and iron levels in plasma and liver of vitamin C deficient guinea pigs after iron overload and desferrioxamine administration.

The effect of desferrioxamine on the reduction of tissue iron and the corresponding level of tissue ascorbic acid have been investigated in female guinea pigs on Vitamin C deficient diet. Plasma and liver AA concentrations were measured after stopping treatment (day 0) and on the following 24 days. Vitamin C intake with the diet enhances rapid absorption of iron into the tissue with corresponding increased catabolism of tissue ascorbic acid. Desferrioxamine reduced tissue iron concentrations without causing pronounced loss of liver ascorbic acid. It is concluded that alterations in tissue ascorbic acid are caused by iron overload in guinea pigs without the pronounced involvement of desferrioxamine.

Vitamin C and weight reducing drugs on brain ascorbic acid in guinea pigs.

A comparison has been made of the effects of d(+) fenfluramine, Mazindol and Diethylpropion on the changes in body weight and brain ascorbic acid concentrations in male and female guinea pigs receiving vitamin C-deficient diet daily with or without daily supplementary vitamin C for 24 days. Bodyweight increases initially; the subsequent decrease was more rapid in scorbutic male than in the female guinea pigs. The weight-reducing drugs prevented the initial rise in weight of these ascorbutic guinea pigs. Fenfluramine caused the greatest fall in weight in both sexes, the effect being more pronounced in the males. Supplementary vitamin C reduced the anti-obesity actions of fenfluramine, Mazindol and Diethylpropion. Brain ascorbic acid level in scorbutic guinea pigs was more significantly reduced by fenfluramine than by either Mazindol or Diethylpropion after 24 days administration. These drugs prevented the rise in brain ascorbic acid normally produced by supplementary vitamin C. The reduction brain ascorbic acid appears to be related to the loss of weight more in the males than in the females.

Anorectic drugs and vitamin C: role in appetite and brain ascorbic acid in guineapigs.

The role of daily administration of anorectic drugs (fenfluramine, mazindol and diethylpropion) with or without Vitamin C supplement, in the appetite and brain ascorbic acid, had been investigated in guineapigs receiving a daily Vitamin C-deficient diet for 24 days. Food intake was reduced by diethylpropion in the scorbutic male and female guineapigs but to a smaller extent by fenfluramine or mazindol. Supplementary Vitamin C daily significantly inhibited the anorectic actions of these drugs. In relation to the brain ascorbic acid level in the scorbutic gunieapigs, the initial stable level of brain ascorbic acid was significantly reduced by fenfluramine in both sexes by day 24, (P less than 0.05). Both mazindol and diethylpropion did not cause such reductions in the initial brain ascorbic acid. The three anorectic drugs prevented the rise in brain ascorbic acid normally associated with supplementary Vitamin C. It appears that brain ascorbic acid level can make metabolic readjustment during anorexia caused by diethylpropion and mazindol but not that caused by fenfluramine in guineapigs.

Regional brain ascorbic acid distribution: its functional relationship to appetite and leptazol-induced convulsions in guinea-pigs.

The distribution of ascorbic acid has been compared in the fore-, mid- and hind-brains of guinea-pigs maintained on a scorbutogenic diet alone, or the diet with supplementary Vitamin C, or the supplemented diet and a terminal convulsant dose of leptazol after 27 days. At the beginning of the investigation, mid-brain ascorbic acid concentrations were similar in both sexes and highest in the mid-brain. After 27 days on the supplemented diet, levels of ascorbic acid were raised in all three brain sections and were still highest in the mid-brains. In the scorbutic group, ascorbic acid concentrations had not changed from control levels in the mid-brain, but had fallen in the other two sections. In a dose-range of 40-60 mg/kg, leptazol caused an increase in convulsive index, and progressive depletion of brain ascorbic acid. No change occurred in fore-brain ascorbic acid, a reduction took place in the hindbrain, and the greatest fall occurred in the mid-brain. It is concluded that ascorbic acid plays an essential role in mid-brain metabolism, and that the convulsant effect of leptazol is influenced by an interaction with brain ascorbic acid.

Tissue ascorbic acid, fenfluramine, and changes in fat metabolism.

Following initial weight gain, reduction in appetite and pronounced weight loss occurred in scorbutic unsupplemented guinea-pigs. Hepatic ascorbic acid levels were significantly reduced and cholesterol concentration increased in the liver. Fenfluramine administration caused immediate loss of weight and appetite in the scorbutic guinea-pigs, these changes being more pronounced in the males. Hepatic ascorbic acid, cholesterol and triglycerides were reduced to lower levels in the fenfluramine-treated scorbutic animals than in the scorbutic guinea-pigs receiving diet alone. In contrast, weight and appetite increased in vitamin-C-supplemented animals while they were receiving fenfluramine. Their hepatic cholesterol and triglyceride levels became significantly reduced. It has been shown that supplementary vitamin C can inhibit the anti-obesity and anorectic actions of fenfluramine and counteract its effect in raising tissue cholesterol.

Vitamin C and the anti-obesity effect of fenfluramine.

Increasing doses of fenfluramine were given to female guinea-pigs on a scorbutogenic diet with or without Ascorbic Acid (AA) supplementation. AA alone increased weight and appetite, hepatic and plasma AA. AA deficiency reduced weight after an initial rise. 10 mg/kg fenfluramine in association with the diet produced a gain in weight. Larger doses caused weight loss and reduced appetite. These effects were prevented by AA supplementation. Fenfluramine reduced hepatic and plasma AA significantly in comparison with the animals receiving the diet alone, or the diet with AA supplementation in the absence of fenfluramine administration. It is concluded that AA release plays an important role in the anti-obesity and anorectic actions of fenfluramine.

Intestinal absorpiton of ascorbic acid and its passage through the lipoid membrane of guinea pigs.

Diffusion of ascorbic acid takes place through intestinal lipoid membrane of guinea-pigs. In consequence, plasma and leucocyte concentrations of ascorbic acid increase. Intestinal absorpiton of ascorbic acid in scorbutic guinea-pigs is impaired in contrast to that in normal and saturated guinea-pigs as shown by the accumulation of ascorbic acid in the intestinal mucosal cells of guinea-pigs.

The buccal absorption of ascorbic acid and its passage through lipoid membrane.

Ascorbic acid concentration was measured in centrifuged and uncentrifuged saliva from normal young adult men and women. The salivary ascorbic acid content of uncentrifuged saliva was significantly higher in women on account of the ascorbic acid contained in the cellular sediment. Ascorbic acid absorption into the buccal mucosa was measured from solutions of pH range 3.4-9.0 held in the mouth for periods of 1-9 minutes. For a constant mouth contact time, increase in pH of the loading solutions resulted in reduction of buccal absorption, and diminishing transfer into the buccal epithelium. Percentage absorption was greater in males than females throughout the pH range. At pH 5, 80% of the loading solution was absorbed after 5 minutes. Diffusion of ascorbic acid through the lipoid membrane was more rapid in males. Female buccal cells had significantly higher ascorbic acid concentrations than male cells. Absorption of laevo and dextro ascorbic acid in human beings can be considered as partitioning into, or passage through, a lipoid phase into the buccal cells. The rate of passage of ascorbic acid into the buccal lining cells under controlled conditions of pH and buccal contact time is pH and concentration dependent in human beings.