The status of vitamins A, B1, B2, B6, B12, C, D, and E as well as that of beta-carotene, biotin, and folate in the blood of over 500 epileptics was compared with that of a normal population. Male and female epileptics showed a poorer supply of vitamins B2, biotin, folate, and 25-hydroxycholecalciferol; the males, of only vitamin B6, B12, and E, and the women, of only vitamin A. Concentrations of beta-carotene and vitamin E in female epileptics were higher. The evaluation of relations between vitamin concentrations and mean daily dose, total dose of anticonvulsants, and duration of therapy suggested a possible influence of anticonvulsant medication on vitamins B1, B2, B6, C, D, E, beta-carotene, biotin, and folate. Concentrations of B vitamins as well as of folate were distinctly lower in patients under monotherapy with enzyme-inducing drugs than in those under valproate sodium. There was no relationship between bone mineral content and 25-hydroxycholecalciferol levels and between the neurographic parameters and the neurotropic vitamins of the B group, which also had no influence on concentration performance. Patients with poorer results in tests of the function of the central and the peripheral nervous system displayed a tendency towards lower vitamin-C levels. There were indications of potential links between immunological status and vitamin B6 and biotin. Males and females with a poorer supply of vitamin C, as well as males with lower riboflavin levels, showed a tendency towards macrocytic anaemia. Cerebellar disturbances were associated with lower concentrations of folate, of vitamin C or D, and possibly of biotin. The incidence of gingival hyperplasia could be linked to riboflavin, to biotin, and possibly also to vitamin C, D, or folate status.
Female rats receiving a diet containing 20% menhaden oil beginning at 10 weeks of age and continuing for 13 weeks had hepatic benzo(a)pyrene [B(a)P] hydroxylase activity significantly higher than similar rats fed diets containing 20% corn oil or 20% oil of evening primrose. Compared to microsomes recovered from rats fed the corn oil diet, a significant increase in microsomal cytochrome P-450 content along with an increase in the activity of cytochrome P-450 mediated ethoxycoumarin O-dealkylase was evident in rats fed menhaden oil. Glutathione S-transferase activity of the cytosol of hepatocytes was increased twofold by the feeding of 20% menhaden oil, compared with the feeding of corn or primrose oil. Administration of 7,12-dimethylbenz(a)anthracene (DMBA) 21 days before instituting the diets enhanced B(a)P hydroxylase in all animals, with the activity greatest in those fed the menhaden oil. DMBA also caused a significant increase in ethoxycoumarin O-dealkylase in rats fed menhaden oil.
Moderate ethanol consumption, at the level of 18% of total energy as part of a liquid diet, was found to result in a significant increase of total vitamin A content in the esophageal mucosa in rats fed normal-zinc-containing or zinc-supplemented diets. There was also an increase in total vitamin A content in the lungs after ethanol consumption, but the change was significant only in the zinc-supplemented group. In the liver, retinyl palmitate plus oleate decreased after ethanol, whereas free retinol, retinyl stearate, and linoleate increased. Ethanol consumption resulted in a modest decrease in hepatic zinc content when expressed per gram of liver, but not per total liver (per 100 gram of body weight). Although chronic ethanol consumption at the level of 18% of total energy did not affect total hepatic vitamin A, there was still a significant increase of vitamin A content in esophagus and lungs.
We examined the effects of dietary vitamin E level on rat lung response to ozone (O3) inhalation. In one study, we fed 1-month-old Sprague-Dawley (SD) rats a test diet containing 0 or 50 IU vitamin E/kg for 2 months, and then exposed one-half of the animals from each dietary group to 0.8 ppm (1,568 micrograms/m3) O3 intermittently (8 hours daily) and the other half to room air for 7 days. After O3 exposure, we found significant increases in marker enzyme activities in rat lungs from both dietary groups relative to corresponding air-exposed controls, but the magnitude of increases was greater for the 0 IU than the 50 IU group. In another study, we fed 1-month-old SD rats a test diet containing 10, 50, or 500 IU vitamin E/kg for 2 months and then exposed one-half of the animals from each dietary group to 0.8 ppm (1,568 micrograms/m3) O3 continuously and the other half to room air for 4 days. The O3 exposure increased the metabolic activities in rat lungs from all three dietary groups relative to corresponding air-exposed controls, but the magnitude of increases was greater for the 10 IU than the 50 IU or 500 IU group, and the difference between the 50 IU and 500 IU groups was small. Because a greater increase in lung metabolism after O3 exposure is thought to be associated with a greater tissue injury, the results suggest that an absence of dietary vitamin E exacerbates lung injury from O3 inhalation, while its presence protects from injury. However, the magnitude of this protective effect does not increase proportionately with increased dietary vitamin E supplementation beyond a certain level.
The effects of various high-fat diets (20% w/w) containing commercially available fats and oils (butter, corn oil, corn oil margarine, canola oil, canola oil margarine, soybean oil, soybean oil margarine, sunflower oil, sunflower oil margarine) on myocardial contractility and morphology and on plasma lipids were investigated in male Sprague-Dawley rats fed the diets for 16 weeks. Diets containing corn oil caused significantly (P less than or equal to .05) higher plasma total cholesterol levels than diets containing butter. Significant differences were also determined in lipoprotein levels. Plasma triglyceride levels were significantly (P less than or equal to .05) higher with butter than with sunflower oil or sunflower margarine. No significant differences among the groups occurred in blood pressure, heart rate, or myocardial contractility. Histological evaluation revealed that animals fed canola oil had the highest incidence and severity of myocarditis and fibrosis and that the degree of cardiac lipidosis was not correlated to the erucic-acid content of the diet. Myocardial damage was significantly (P less than or equal to .05) negatively correlated with stearic and palmitic acids and positively correlated with oleic acid. The results indicate that diets low in saturated fats may have adverse long-term effects on the heart.
A study was undertaken to assay the various phase I and phase II drug metabolising enzymes in zinc deficiency. Male weanling Fischer rats were subjected to zinc deficiency for a period of 7 weeks. Zinc levels in the control and deficient diets were 30 mg and 1.1 mg/kg diet, respectively. At the end of the experimental period, the activities of various hepatic cytosolic and microsomal enzymes were estimated. It was observed that the activities of microsomal epoxide hydrolase (with benz(a)pyrene 4-5 oxide as substrate), uridine diphospho glucuronyl transferase (with 1-naphthol as substrate) and cytosolic glutathione-S-transferase (with chlorodinitrobenzene as substrate) were altered exclusively due to zinc deficiency. There was a change in the activities of the following enzymes, which could be due either to zinc deficiency and/or food restriction: 1) aryl hydrocarbon hydroxylase; 2) cytochrome b; 3) cytochrome c; and 4) cytochrome b5. Other enzymes studied, i.e., cytosolic epoxide hydrolases, microsomal EHSTO, and UDPGT testosterone were not different in the control and experimental groups. The results are discussed in relation to the activation of carcinogens and neoplastic formation in zinc deficiency.
Absorption and bioavailability of theophylline from a sustained-release gelatin capsule were investigated in 10 male rabbits after oral administration (20 mg/kg), with and without a ground capsicum fruit suspension. Comparison of pharmacokinetic parameters showed that the concomitant absorption of capsicum increases areas under plasma curves (from 86.06 +/- 9.78 mg H/liter to 138.32 +/- 17.27 mg H/liter, P less than 0.001), peak plasma levels (from 6.65 +/- 0.76 to 8.78 +/- 0.98 mg/liter, P less than 0.01), and mean residence times (from 14.94 +/- 2.97 to 20.98 +/- 5.75 H, P less than 0.001). A second administration of the capsicum suspension, 11 hours after dosing, produced a new rise of theophylline plasma levels in every rabbit. The variations in pharmacokinetic and bioavailability parameters are discussed in accordance with the mechanisms of action of capsaicin, an active compound present in capsicum fruit.
Female Swiss mice were exposed to zinc chloride (0 to 500 ug/mL) or copper sulfate (0 to 200 ug/mL) in their drinking water for 15 weeks. After 3 weeks of the exposure period, the mice were administered urethan (1.5 mg/g) intraperitoneally. Urethan-induced pulmonary adenoma formation was evaluated 12 weeks later. Zinc exposure increased the number of adenomas produced but reduced the mean tumor diameter in the intermediate treatment groups, 50 and 200 ug/mL. Exposure to copper had no effect on tumor size or on tumor number. Weight gains in the mice were not affected by copper or zinc treatment, although a dose-dependent reduction in water consumption was observed with copper. Water consumption in mice exposed to zinc was elevated in one treatment group (50 ug/mL). Urethan-induced sleeping times, which reflect the rate of urethan excretion, were prolonged by zinc exposure but were unaffected by copper exposure. This finding suggests that zinc exposure impairs the elimination of urethan and enhances its carcinogenic activity, which is manifested by increased tumor formation.
By utilising an in vivo technique the effects of amoxicillin, cephalexin, and tetracycline-HCl on intestinal L-leucine absorption were studied in the rat. The results showed that amoxicillin caused a time-dependent and reversible inhibition of L-leucine transport while the inhibition induced by the other two antibiotics tested was not reversible. Light microscopic studies revealed that the three antibiotics were without effect on intestinal mucosal morphology.
Carbon tetrachloride-mediated hepatotoxicity in mice was influenced by two standard, commercially available diets and by a corn oil treatment vehicle. Animals maintained on Purina 5001 diet were less sensitive than animals maintained on Teklad LM-485 diet to hepatic intoxication by carbon tetrachloride (CCl4). Lower sensitivity of the Purina group was evidenced by significantly lower plasma alanine aminotransferase (ALT) levels and higher hepatic cytochrome P-450 levels at all dosages of CCl4. In addition to the diets, the nature of the corn oil vehicle affected toxicological responses of mice to CCl4. When the vehicle from which tocopherols had been extracted was used, CCl4 elicited about twice the levels of plasma ALT than when nonextracted corn oil was used. In conclusion, the nature of the animal diet and treatment vehicle not only can influence toxicological response, but also can be important considerations in the interpretation of toxicological data.
Excessive ethanol intake during pregnancy can cause birth defects in humans and is referred to as fetal alcohol syndrome (FAS). Because of the characteristic changes that are similar in FAS and zinc (Zn) deficiency, we have examined the role of Zn nutriture in the teratogenicity of ethanol in Sprague-Dawley rats. Female Sprague-Dawley rats were adapted to liquid diets containing Zn at 2 micrograms/ml (LZn), 30 micrograms/ml (AZn), or 300 micrograms/ml (HZn); ethanol contributed either 0% or 36% of kilocalories. Ethanol consumption resulted in reduced fetal growth and retarded skeletal development. Ethanol had no effect on whole body fetal Zn concentrations; however, copper (Cu) deficiency was induced in the HZn fetuses. Ethanol consumption resulted in higher than normal fetal liver CuZnSOD activity in the LZn and AZn groups. Fetuses from HZn dams showed no ethanol effect on CuZnSOD activity, suggesting that the low availability of Cu to the fetus prevented the increase in CuZnSOD activity in response to ethanol. The increase in the activity of fetal CuZnSOD in LZn and AZn groups is consistent with the concept that the metabolism of ethanol results in free radical generation in fetal tissue. Because excessive free radical levels may result in tissue damage, this may be one mechanism contributing to the expression of FAS.
The effects of commercially available calcium supplements (calcium carbonate, oyster shell, chelated calcium and magnesium, calcium phosphate dibasic) and milk on tissue levels and apparent absorption of calcium, magnesium, phosphorus, iron, zinc, and copper were evaluated with rats that had been made anemic by dietary iron depletion. Hematocrits of anemic rats fed the chelated calcium and magnesium were restored more slowly than rats fed the other calcium sources. The rats fed chelated calcium and magnesium also retained less iron in their livers than rats fed calcium phosphate dibasic, oyster shells, or calcium carbonate and retained less calcium in bone than rats fed milk, oyster shells, or calcium phosphate dibasic. Rats fed calcium phosphate dibasic had on average 40-fold higher levels of calcium in their kidneys than rats fed the other diets. The molar ratio of additional calcium and phosphorus in kidneys of these rats was 3:2.
Acetaminophen (ACAP) was fed to adult Swiss-Webster mice for 4 weeks to examine the effect of prolonged ACAP ingestion on hepatic reduced glutathione (GSH) concentrations. In the first experiment, male and female mice were pair-fed diets containing ACAP at levels of 0.0 (control), 0.3, 0.6, and 1.0% of diet on a dry weight basis with the total sulfur-amino acids provided at 0.5% of the diet. Hepatic GSH was depleted, and the percentage of dose excreted as the urinary ACAP-GSH-derived conjugate increased in a dose-dependent manner with increasing ACAP. Serum glutamic-pyruvic transaminase activity, relative liver weight, and hepatic microsomal protein content increased in the group given 1.0% ACAP, but microsomal aniline hydroxylation decreased. In the second experiment, adult male mice were fed ad libitum diets containing 0.0 or 0.6% ACAP with total L-methionine provided at 0.25, 0.5 (requirement level), or 1.0%. Hepatic GSH was markedly depleted 1 week after initiation of ACAP treatment in all groups except those receiving 1.0% methionine. This reduction persisted throughout the 4-week treatment period. After 4 weeks, liver cysteine was also reduced as a result of ACAP ingestion and methionine deficiency, whereas serum inorganic sulfate concentration was not changed. Reduction in hepatic cysteine levels was also prevented by 1.0% dietary methionine. The dose-dependent depletion of GSH, the trend toward an increase in ACAP-GSH-derived conjugate excretion, and the prevention of GSH depletion by providing dietary methionine in excess of requirement indicate that prolonged ingestion of ACAP may increase the requirement for sulfur-containing amino acids and limit the availability of methionine and cysteine for protein synthesis, methylation reactions, and drug detoxification.
The effects of zinc deficiency on ethanol-induced ulcers were studied. Rats fed with zinc-deficient diets for 5 weeks showed markedly lowered serum zinc levels and body weights. Ethanol 30% given orally produced gastric mucosal lesions and reduced the glutathione content in the gastric glandular mucosa in their pair-fed non-zinc-deficient controls. Zinc deficiency potentiated the glutathione-depleting and ulcer-producing effects of ethanol. N-acetylcysteine, a sulfhydryl-containing agent, protected non-zinc-deficient rats from lesions produced by 50% ethanol, whereas N-ethylmaleimide, a sulfhydryl-blocking agent, worsened ulceration. It appears that zinc deficiency intensifies ethanol-induced ulceration by permitting greater depletion of the glutathione content in the stomach.
Liver microsomes from obese and control Sprague-Dawley rats were compared for cytochrome P-450 content and the ability to metabolize various prototype substrates. Over a 40-week period, the obesity-producing energy-dense diet increased average total body mass by 50%, liver mass by 32%, and body fat mass by 292%. Spectrally detectable cytochrome P-450 per mg protein increased by 36% in hepatic microsomes from obese rats. The livers from obese rats also contained more cytochrome P-450 (87%), while microsomal protein, NADPH-cytochrome c reductase, aryl hydrocarbon hydroxylase, and UDP-glucuronosyl transferase per organ rose slightly (12-40%) but not significantly. No change in the specific activities of these enzymes occurred. Young and adult rats were transferred from pellet diet to energy-dense diet for 3 weeks to examine the influence of diet vs. obesity. This short-term dietary change increased microsomal protein per g liver as well as cytochrome P-450 per liver, per g liver, and per mg protein. Adult animals increased in body weight by 24%, making them overweight and borderline obese. However, young animals showed no increase in body or liver weight, suggesting a direct effect of the energy-dense diet on liver P-450. Dietary obesity thus increased both the relative and total amounts of liver cytochrome P-450 in rats, but not the specific activities of other enzymes. These changes in cytochrome P-450 are consistent with the increased clearance seen for several oxidized drugs in obese humans and suggest that the obese overfed rat represents a useful animal model.
In the elderly, drug treatment is used for the prevention and control of cardiovascular disease. Prevention of cardiovascular disease includes management of hypercholesterolemia to reduce risk of myocardial infarction, treatment of acute myocardial infarction to reduce the risk of recurrence, and treatment of hypertension to reduce the risk of hypertensive heart disease and stroke. Management of chronic cardiovascular disease with permanent disability is the major therapeutic goal. The most commonly treated disorders of the heart and peripheral vascular system include congestive heart failure, arrhythmias, angina, and thromboses. Reduction of plasma lipid levels may be undertaken by drug therapy as a means of preventing myocardial infarction.
Elderly diabetics take more drugs than other groups of elderly patients. Their multiple drug use is largely explained by the drugs that they take for complications of their primary disease; these include cardiovascular drugs for macrovascular disease and antibiotics for secondary infections. They also take more drugs for control of other conditions that are etiologically associated with the development and progression of their diabetes, including antihypertensive agents, antilipemic agents and steroids, and nonsteroidal antiinflammatory drugs (NSAIDs), which are taken for relief of joint pain that is intensified by arthritic joints bearing excess weight. Drugs taken by elderly diabetics that contribute to the high prevalence of drug-nutrient interactions include those taken as antidiabetic agents, including both insulin and sulfonylureas as well as calcium channel blockers; they also include thiazides, loop diuretics, sulfa drugs, cephalosporin antibiotics, tetracyclines, antifungal agents, cholestyramine and colestipol, niacin, prednisone and other corticosteroids, and NSAIDs. These drugs and drug combinations contribute to the risk of hyperglycemia, which can cause nonketotic hyperglycemia in the elderly; to the risk of hypoglycemia, which in the elderly carries the risk of inducing pseudo-stroke; to the risk of drug-induced nutritional deficiencies from antilipemics and cephalosporins, which can induce vitamin K deficiency; to the risk of acute incompatibility reactions, including flush reactions from chlorpropamide, niacin, and calcium channel blockers; and to the risk of edema, anemia, and hyperkalemia from NSAIDs.(ABSTRACT TRUNCATED AT 250 WORDS)
Weanling male CD-1 mice were fed low-iron or iron-supplemented diets for 31 days. Mice fed the low-iron diet exhibited typical signs of iron deficiency, which included reduced weight gains (P = 0.0041) and anemia (P less than 0.0001). The effect of iron deficiency on antibody production, lymphocyte blastogenesis, and sensitivity to endotoxin were evaluated. Antibody production against sheep red blood cells, a T-lymphocyte dependent response, was reduced in iron-deficient mice (P = 0.0067). In contrast, antibody production against dinitrophenyl-ficoll, a T-lymphocyte-independent response, was not affected by iron deficiency (P = 0.291). Iron deficiency reduced T-lymphocyte blastogenesis induced by concanavalin A (P = 0.011), but had no effect on B-lymphocyte blastogenesis induced by Escherichia coli lipopolysaccharide (P = 0.662). These results indicate that the immunosuppressive effects of iron deficiency are related to T-lymphocyte function associated with lymphocyte proliferation and antibody production. A significantly increased susceptibility to endotoxin, a T-lymphocyte-independent response involving nonspecific defense mechanisms, was not observed in iron-deficient mice. Mortality associated with endotoxin was 14.2% in the iron-deficient mice as compared to 35% in the iron-replete mice (P = 0.079).
Ingestion of cadmium (Cd) acetate in deionized drinking water (1 ppm) in rabbits resulted in the development of hypertension and increased left ventricular mass similar to what was observed in experimental renal hypertension (Grollman technique). Regardless of the approach, mean arterial pressures (MAP) of at least 50 mm Hg greater than those of controls developed over a 34-day period. Increased left ventricular mass relative to body weight was found in both hypertensive groups. However, only an increase in renal mass was observed in unilaterally nephrectomized animals. The increased mass of hearts and kidneys that was detected after an approximately 1-month period attests to the severity of these forms of experimental hypertension. These results demonstrate that the ingestion of drinking water contaminated with Cd can cause hypertension and an increase in left ventricular mass over a short time period in rabbits.
Studies were conducted to investigate the effects of lead and niacin on tryptophan and serotonin metabolism in growing broiler chicks. A low-niacin basal diet based on soybean meal and glucose was supplemented with either 40 ppm niacin/kg feed or 2,000 ppm lead, as lead acetate trihydrate, or a combination of the two in a 2 x 2 factorial arrangement. The experimental diets were fed from 1 day to 3 weeks of age. The activities of several enzymes involved in tryptophan and serotonin metabolism were assayed in chicks fed each of the experimental diets. Lead reduced the activity of liver tryptophan pyrrolase but had no effect on the activity of hepatic picolinic carboxylase. Low dietary niacin had no effect on the activity of either of these enzymes. Brainstem tryptophan 5-hydroxylase activity was unaltered by either lead or niacin. Brain and liver monoamine oxidase activity was reduced by lead but was not affected by niacin. No interactions of lead and niacin were observed with any of the enzymes examined. Lead had no consistent effect on brain serotonin (5-HT) steady-state level, but it increased the level of the major metabolite of 5-HT, 5-hydroxyindoleacetic acid (5-HIAA). Monoamine oxidase blockade failed to reduce the elevated 5-HIAA level in lead-treated chicks. The drug probenecid produced an increase in 5-HIAA that was comparable to the increase caused by lead. The effects of probenecid and lead were additive. It is concluded that lead significantly altered the activity of several enzymes involved with tryptophan metabolism, whereas the dietary niacin levels employed were without effect. Additionally, lead caused the accumulation of 5-HIAA in the brain, which appeared to result from inhibition of the probenecid-sensitive acid transport system.
