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.

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Abstract-When dextran "S-sulfates (DSs), anticoagulants and antilipemic agents, were intravenously given to rats, the specific radioactivity was five to twenty times higher in the lysosomal than in the other subcellular fractions of liver, but the counts in this fraction were only 10% of total radioactivity distributed to the liver. Therefore, we investigated the biliary excretion of 35S-DSs with a similar sulfur content of 18% and three different average molecular weights (AMW) of 3000, 20,000, and 200,000. The excretion rate was about 2 % of the radioactivity given, per hour, after intravenous administration of35S-DS with AMW of 20,000, 10 mg/kg. At this time, acid phosphatase activity and calcium content of bile also were increased, and well correlated with the amount of the radioactivity excreted to bile. The amount of the radioactivity distributed to the lysosomal fraction is correlated with the enhanced activities of Nat-K+-dependent and Ca2+-activated ATPase in this fraction, indexes of endocytotic and exocytotic transports.DSs significantly enhanced 45Ca levels of the lysosomal, but not the cytosol fraction when 45CaCl2 was given alone or simultaneously with DSs. According to our previous reports that DSs are transferred to the lysosomal fraction of liver and intestinal mucosa by endocytosis, the present results suggest that DSs, especially with high AMW and which are distributed to liver lysosomes are rapidly excreted into bile by exocytosis and accompanied by calcium and lysosomal enzymes.Macromolecules can enter into cells (1-3). DeDuve and Wattiaux (4) reported that dextran, a high molecular weight polysaccharide, is transported to liver cells and accumulates within endocytotic granules in the cytosol. Most of the granules can be collected in the lysosomal fraction by subcellular fractionation (5). Aronson and Davidson (6) and our group (7) have indicated that acid polysaccharides, chondroitin sulfates and dextran sulfates (DSs), are found in the lysosomal fraction of rat liver after intravenous administration.When 35S-labeled DS with an average molecular weight of 200,000 was given intraduodenally, the lysosomal fraction of intestinal mucosa contained 40 % of the tissue radioactivity (8). In the liver lysosomal fraction only 10 % of the tissue radioactivity was found after intravenous administration of the DS (7).Acid polysaccharides distributed to liver lysosomes are eliminated by catabolism (6) and biliary excretion. DeDuve and Wattiaux (4) indicated that dextran which was transferred to liver lysosomes is rapidly excreted to bile. Therefore, the difference in lysosome/ tissue ratio of the radioactivity between liver and intestinal mucosa may be due to the rapid biliary excretion of 35S-DSs distributed to liver lysosomes. Thus, we examined the biliary excretion of DSs with a similar sulfur content of 18 % and three different average molecular weights of 3000, 20,000, and 200,000. Our findings are reported herein.

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