Drug-nutrient interactions最新文献

The effect of pair feeding of euthyroid rats compared with propylthiouracil (PTU) treated rats on acetaminophen (APAP)-induced hepatotoxicity was studied. Also, the effect of food deprivation of both the euthyroid and PTU-induced hypothyroid rats for 24 h, as well as forced feeding of the euthyroid rats after a toxic dose of APAP, was determined. Pair feeding decreased both protein and energy intake compared with ad libitum-fed controls and resulted in decreased growth rate similar to that for the PTU treated rats. In contrast to the protective effect of PTU pretreatment, decreased protein energy intake by the euthyroid rats either tended to make them more susceptible to acetaminophen-induced hepatotoxicity or had no effect as assessed by elevation of serum transaminases (SGOT,SGPT) and by hepatic necrotic score. Pair feeding also significantly altered drug disposition with an increase in the molar ratio of urinary APAP-mercapturic acid conjugate, but not the absolute amount, suggesting possible increased cytochrome P-450 dependent drug metabolizing enzyme activity. Compared with PTU-fed, in the pair-fed the molar ratio of glucuronide conjugate decreased and sulfate conjugate increased. Hepatic reduced glutathione (GSH) concentrations before and 4 h after a toxic dose of acetaminophen administration were higher in the PTU pretreated compared with euthyroid rats. Fasting of the PTU pretreated rats for 24 h after acetaminophen administration abolished the PTU-induced protective effect. Forced feeding of the euthyroid rats after a toxic dose of acetaminophen increased rather than decreased the toxicity when compared with euthyroid ad libitum-fed rats. Data suggest that higher concentrations of hepatic glutathione in the PTU pretreated compared with euthyroid rats before and 4 h after acetaminophen administration contribute to PTU-induced protection. Forced feeding of rats when the liver is severely damaged and its function compromised is harmful rather than protective. We conclude that the nutritional state of the animal significantly influences drug toxicity and should be taken into consideration in designing drug therapy and evaluation of drug toxicity.

Weanling female Swiss mice were fed copper-deficient or copper-replete diets for 28 days. Mice fed the copper-deficient diet exhibited typical signs copper deficiency, which included reduced weight gains, anemia, and low liver copper concentrations. The effect of copper deficiency on antibody production, in particular, T-lymphocyte dependent and independent antibody responses, lymphocyte blastogenesis, and sensitivity to endotoxin were evaluated. Antibody production against sheep red blood cells, a T-lymphocyte dependent response, was suppressed in copper-deficient mice (P less than .0001). In contrast, antibody production against dinitrophenyl-ficoll, a T-lymphocyte independent response was not altered by copper deficiency (P = 0.90). Lymphocyte blastogenesis studies demonstrated that copper deficiency did not alter T-lymphocyte blastogenesis induced by concanavalin A (P = 0.27) or B-lymphocyte blastogenesis induced by Escherichia coli lipopolysaccharide (P = 0.40). These results indicate that the immunosuppressive effects are not due to an impairment of lymphocyte blastogenesis, an intermediate step involved in the generation of an immune response, but rather are a manifestation of impaired T-lymphocyte function associated with antibody production. Increased susceptibility to endotoxin, involving nonspecific defense mechanisms, was also observed in copper-deficient mice. Mortality associated with the endotoxin was 68% in the copper-deficient mice as compared to 35% in the copper-replete mice (P = 0.0026). Impaired T-lymphocyte dependent antibody production and enhanced susceptibility to endotoxin were observed in copper-deficient mice exhibiting classical manifestations of copper deficiency.

Interactive combinations of altered zinc and thyroid states were studied in rats to assess pathophysiologic effects. Clinical signs of zinc deficiency or thyroid alteration were limited to effects on growth rate. Changes in organ and glandular weights and serum thyrotropin levels reflected changes in serum thyroid hormone concentrations. Significantly (probability less than .001), zinc-deficient rats had enhanced hepatic thyroxine-5'-monodeiodinase activity. In addition, the zinc-deficient state was found to be protective against thiouracil-induced suppression of the microsomal-monooxygenase and thyroxine-5'-monodeiodinase enzyme complex. This protective effect was evident by greater thyroxine-5'-monodeiodinase and reduced nicotinamide-adenine dinucleotide phosphate cytochrome c reductase activities, as well as cytochrome P-450 content, in zinc-deficient/thiouracil-treated animals. Thus, the enzyme complex had increased triiodothyronine-generating capacity in conditions of zinc deficiency, which may be important because of the greater biological reactivity of triiodothyronine. Primary zinc deficiency conditions of the magnitude seen in this study and in this-age rat did not appear to alter serum thyroid hormone levels or organ/glandular function. However, concurrent zinc deficiency and altered thyroid status did change thyroid hormone response and disposition, which may be important to populations at risk because of thyroid dysfunctional states.

Thirty-four Wistar rats were fed a marginal or normal vitamin A diet and received daily for 14 days an intragastric intubation of oil supplemented with 0, 20, or 60 mg X kg-1 of cyclosporine A. The hepatic content and concentration of vitamin A were significantly decreased by cyclosporine treatment, whereas no modification occurred in kidney or serum vitamin A levels. No induction of hepatic cytochrome P-450 was observed in treated animals. These results suggest that cyclosporine interferes with vitamin A stores; thus, vitamin A supplementation may be useful in patients receiving cyclosporine therapy. Drug-metabolizing enzymes, which are cytochrome P-450 dependent, did not seem to be involved in the hepatic vitamin A decrease observed.

Female Swiss were exposed to sodium selenite (3 micrograms/ml selenium content) and sodium arsenate (80 micrograms/ml arsenic content) in the drinking water individually or in combination on alternate days for 15 weeks. Comparable water consumption was observed in all individual or combined metal-exposure groups. After 3 weeks of metal exposure, the mice were administered urethan (1.5 mg/g) intraperitoneally. Pulmonary adenoma formation was evaluated 12 weeks later. Arsenic exposure reduced the tumor incidence (P = 0.0046) and tumor size (P less than 0.0001). Selenium exposure did not alter the tumor incidence but caused a reduction in tumor size (P = 0.022). No selenium-arsenic interactions associated with tumor size or number were observed. Urethan-induced sleeping times were unaffected by exposure to selenium (P = 0.832) or arsenic (P = 0.42), although combined metal exposure reduced the duration of urethan-induced sleep (P = 0.029) as compared to the individual metal exposures. This metal-metal interaction, which appeared to enhance the rate of urethan elimination as indicated by the reduced sleeping time, did not influence adenoma formation significantly.

Hepatic metabolism of the labile methyl group donor, S-adenosylmethionine (SAM), was investigated in rats fed toxic levels of retinol (1,000 IU/g of diet) since this treatment is known to decrease hepatic SAM concentration. The turnover rate of the hepatic SAM pool was not affected by the excess retinol, but the use of SAM as a labile methyl donor was restricted. Incorporation of the methyl group into phosphatidylcholine was reduced by 51% and oxidation of the methyl group to CO2 was decreased by 40%. In addition, the concentrations of cysteine and cystine, which are synthesized subsequent to demethylation of SAM, were reduced by 32% and 30%, respectively, in liver of high-retinol-fed rats, while methionine concentration was unchanged. The toxic level of dietary retinol may bring about a shift in the metabolism of SAM from transmethylation toward pathways that regenerate methionine via 5'-methylthioadenosine.

The effects of dietary magnesium (Mg) deficiency on histamine metabolism were studied. Young Wistar rats were fed a Mg-deficient diet (0.001% Mg diet) ad libitum for 8 days with control groups (0.07% Mg diet), food-restricted groups (0.21% Mg diet, but restricted to 5 g/rat/day), and refeeding groups (0.001% Mg diet for 6 days ad libitum, after that fed with a 0.21% Mg diet ad libitum for 2 days). Compared to the other groups, the plasma Mg level was markedly lower in the Mg-deficient group. A return from the lower Mg level to the controls took place after feeding them a 0.21% Mg diet for 2 days. Urinary histamine level increased rapidly after 4 days and reached a maximum on the eighth day of Mg deficiency. The high urinary histamine level in Mg-deficient rats decreased rapidly after feeding them a 0.21% Mg diet for 2 days. Histamine contents in some tissues increased on the eighth day of Mg deficiency. Other groups showed no significant change. The increased histamine content in Mg-deficient rats showed a tendency to return to control levels after feeding them a 0.21% Mg diet for 2 days. Histidine decarboxylase (HDC) activity in some tissues of Mg-deficient rats increased markedly. The increased HDC activity dropped nearly to control levels after feeding them a 0.21% Mg diet for 2 days. Diamine oxidase (DAO) activity in the duodenum was high in control rats. Duodenal DAO activity decreased gradually and reached half the value of controls on the eighth day of Mg deficiency.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of amoxicillin on galactose absorption across rat small intestine was investigated by using in vivo and in vitro techniques. Amoxicillin caused a dose-related, time-dependent, and reversible inhibition in intestinal sugar transport. Intestinal galactose transport was not affected when the drug was perfused in an adjacent loop. Also, intestinal oxygen consumption was not impaired by amoxicillin. Amoxicillin decreased the apparent affinity of galactose for the carrier system, while both its maximum absorptive capacity and the phlorhizin-insensitive component of sugar absorption remained unaltered.