Toxicity and Metabolism of Drugs in Relation to Dietary Protein

Abstract

It was demonstrated that the toxicities of various drugs are often related to the rate of metabolism of the drugs and to the activity of drug-metabolizing enzymes of liver micro somes (1-6). In a previous paper, it was briefly reported that the oxidation of pento barbital, strychnine and meprobamate was markedly decreased in the immature female rats by the feeding on low protein diet or non-protein diet (7).The purpose of present study is to investigate the effect of high and low protein diet on the toxicities of various drugs in relation to the drug-metabolizing activities of liver microsomes, and to investigate whether the alternation in the drug-metabolizing activities may be correlated to the activities of microsomal NADPH-linked electron transport system.Since there are marked sex differences in the alternations in the activities of drug metabolizing enzymes in the rats under some unphysiological states, the effect of diets of different protein contents on the toxicity and metabolism of drugs was comparatively investigated in male and female rats (8-12). METHODSMale and female rats of Wistar strain, weighing about 170 g and 150 g, respectively, were used. The rats were fed diets of 50%, 18%, 10% or 5% protein content for 2 weeks or fed non-protein diet for 4 days before sacrifice. The composition of the standard diet was as follows: 18% casein, 300/ corn starch, 15% glucose, 10% sucrose, 10% corn oil, 10% wood pulp and salt mixture and vitamins.The diets of various protein content were made by changing the content of casein with glucose.The toxicities of strychnine, octamethylpyrophosphoramide (OMPA), pentobarbital and zoxazolamine were determined by the intraperitoneal injection of the drugs. The metabolism in vivo of pentobarbital was determined by measuring the rate of decrease in the concentration of pentobarbital in the serum and brain.

Influence of dietary protein and carbohydrate on phenytoin metabolism in man.

“…Dietary composition has been shown to be an important environmental determinant in drug metabolism. A reduction in dietary protein intake decreases microsomal oxidations of various substrates and increases the toxicity of drugs (Kato, Oshima & Tomizawa, 1968) and pesticides (Boyd & Dubos, 1969). An increase in dietary protein intake increases drug metabolism (Kato et al, 1968).…”

“…A reduction in dietary protein intake decreases microsomal oxidations of various substrates and increases the toxicity of drugs (Kato, Oshima & Tomizawa, 1968) and pesticides (Boyd & Dubos, 1969). An increase in dietary protein intake increases drug metabolism (Kato et al, 1968). A high carbohydrate intake decreases liver mono-oxygenase activities (Strother, Throckmorton & Herzer, 1971).…”

Interactions between nutritional factors and drug biotransformations in man.

“…The decreases in microsomal oxidations are accompanied by decreases in hepatic content of the hemeprotein cytochrome P-450, the terminal oxidase of the hepatic mixed function oxidase system. In contrast, the metabolism of the drugs indicated is increased in rats fed a high protein diet (2). A high carbohydrate intake has been shown to increase barbiturate-induced sleeping time in mice (5), to cause cessation of lipid peroxidase activity, and to cause a considerable decrease in liver mixed function oxidase activity in rats (6).…”

Drug Metabolism in Tumor-Bearlng Rats

“…This fact is, especially, important for some drugs which should be converted to the active metabolite in vivo (5-7). Some carcinogenic and carcinostatic compounds, such as dimethylnitrosamine, 2-acethylaminofluorene, 4-nitroquinoline N oxide and cyclophosphoramide, belong to this group (8-11).The activities of drug-metabolizing enzymes of liver microsomes are markedly altered by several factors, such as, the administrations of different kind of lipid soluble compounds and anabolic hormones, starvation, low protein diet, formaline and adrenaline stress, al loxan diabetes, hyperthyroidism, adrenalectomy, viral hepatitis and hepatectomy (1,3,(12)(13)(14)(15)(16)(17)(18)(19)(20).In a preliminary work,* we observed a decrease in the metabolism of pentobarbital, meprobamate and strychnine in Walker 256 carcinosarcoma bearing male rats. How ever, there are clear sex difference in the alternation of activities of drug-metabolizing enzymes by the non-physiological conditions.…”