Mixed Function Oxidase System In Rats Research Articles

Effects of Excess Dietary Tyrosine on Cholesterol, Bile Acid Metabolism and Mixed-Function Oxidase System in Rats

Excess dietary tyrosine (12%) caused hypercholesterolemia in male Wistar rats and significantly increased cytochrome P-450 and b5 contents. Bile flow and biliary output of total bile acids were significantly increased in rats fed this diet. Biliary output of cholesterol was not significantly altered, whereas that of taurocholic acid was significantly increased. Excess dietary tyrosine significantly decreased the fecal excretion of neutral steroids, whereas total steroid excretion was not significantly changed. The present results indicate that excess dietary tyrosine causes hypercholesterolemia without modifying the fecal total steroid excretion, thus supporting our previous hypothesis that stimulated synthesis of cholesterol is a main reason why excess dietary tyrosine leads to hypercholesterolemia.

Effects of alkyl phosphorothioates on the hepatic microsomal mixed-function oxidase system in rats: Inhibition of drug-metabolizing enzyme activity and selective increase of NADPH-cytochrome c reductase activity

Four series of alkyl phosphorothioates were administered to adult male rats by intraperitoneal injection, and their influences on the drug-metabolizing enzyme system in hepatic microsomes were examined. Among the alkyl phosphorothioates tested, O, O, O-trialkyl phosphorothioates (I) and O, O, S-trialkyl phosphorodithioates (II) significantly decreased hepatic microsomal cytochrome P-450 content and the metabolism of aniline and aminopyrine. Six hours after administration, triethyl compounds were the most effective of the trialkyl esters tested. In experiments on rats pretreated with phenobarbital or 3-methylcholanthrene, the inhibitory effects of triethyl esters were increased strongly by phenobarbital pretreatment and decreased by 3-methylcholanthrene. After the administration of I, a selective increase of NADPH-cytochrome c reductase activity was also observed. In the phenobarbital-pretreated rats, no further increase of NADPH-cytochrome c reductase activity was observed as a result of the administration of I. Except for the two dibutyl esters, O, O-dialkyl phosphorothioates (III) and O, O-dialkyl phosphorodithioates (IV) caused no significant inhibitory effect on the drug-metabolizing enzyme system under the same conditions.

Interaction of the oncolytic drug, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea with the mixed-function oxidase system in rats

Effects of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) on the hepatic mixed-function oxidase system in male rats were studied both in vivo and in vitro. A single dose of CCNU (40 mg/kg) caused a significant reduction in hepatic mixed-function oxidase activities within 3 days after administration. The depression was prolonged for cytochrome P-450, total haem and the metabolism of several type I substrates lasting up to 10 weeks after a single dose. By contrast, aniline hydroxylase, cytochrome b 5 and NADPH-cytochrome c reductase activities returned to near control levels after week two. Microsomal enzymes in the kidneys of treated animals however, were unaltered. Serum glutamic pyruvic and glutamic oxaloacetic transaminase and bilirubin levels, indicators of hepatotoxicity, were greatly elevated 3 days after CCNU treatment. These parameters fell rapidly but were still above control levels to the end of the 10-week study. When added in vitro, CCNU reduced apparent cytochrome P-450 content and the metabolism of type I substrates in microsomes from untreated, phenobarbital (PB) and 3-methylcholanthrene (3-MC)-pretreated rats. Total haem and NADPH-cytochrome c reductase were not affected whereas aniline hydroxylase activity was activated. CCNU interacted with hepatic microsomes to produce a type I difference spectrum.

Dietary Influences on the Hepatic MixedFunction Oxidase System in the Rat After Portacaval Anastomosis

Studies were undertaken to determine the influence of diet on the hepatic mixed-function oxidase system in rats after portacaval anastomosis. Male rats fed either a cereal-based or purified diet underwent portacaval anastomosis. Weight gain after surgery was highly dependent on the diet. Because rats fed the cereal-based diet weighed 50% less at 4-5 wk after portacaval shunt surgery than unoperated controls fed the same diet, pair-fed unoperated controls were also studied. Rats fed the purified diet grew normally after shunting and therefore studies with this diet did not require pair-fed controls. Shunted rats fed the cereal-based diet had lower liver weights, hepatic microsomal protein concentrations, ethylmorphine N-demethylase, aniline hydroxylase, and cytochromes P450 and b5 when compared with corresponding values in unoperated controls fed the same diet ad libitum; comparisons with pair-fed controls indicated that decreased intake of the cereal-based diet could account for part but not all of the changes seen after portacaval anastomosis. It was shown in rats fed the purified diet that sham operation had no effect on the mixed-function oxidase system, whereas portacaval anastomosis resulted in reduced liver weight, microsomal protein, ethylmorphine N-demethylase, aniline hydroxylase, and cytochrome P450. In comparing shunted rats fed the two types of diet, in contrast with the effects of these diets in normal rats, these hepatic microsomal mixed-function oxidase system components were generally lower in the shunted rats fed the cereal diet. It is concluded that although decreased mixed-function oxidase activity occurs after portacaval anastomosis in the rat, the diet can have an additional substantial influence. Dietary influences on drug oxidations may be an important consideration in drug therapy after portacaval anastomosis.