ABSTRACT
5 days' exposure of rats to daily doses of 400 mg/kg body wt. of chlordiazepoxide, diazepam and oxazepam stimulated the microsomal metabolism in the liver, as evidenced by acceleration of both p-hydroxylation of aniline and hydroxylation of benzene. The effect was accompanied by an increased concentration of liver microsomal protein and by the development of tolerance to the drugs. Similar effects were found after exposure of rats to lower doses of the drugs. The metabolism of aniline in vivo in rats treated with chlordiazepoxide was accelerated; this was correlated with development of tolerance to these drugs. It is suggested that both the stimulation of microsomal metabolism and the development of tolerance are associated with the induction of microsomal drug-metabolizing enzymes.
Subject(s)
Chlordiazepoxide/pharmacology , Diazepam/pharmacology , Microsomes, Liver/enzymology , Mixed Function Oxygenases/metabolism , Oxazepam/pharmacology , Oxidoreductases/metabolism , Aniline Compounds/metabolism , Animals , Benzene/metabolism , Body Temperature/drug effects , Drug Tolerance , Hydroxylation , Kinetics , Male , Microsomes, Liver/drug effects , Muscle Contraction/drug effects , Organ Size/drug effects , Proteins/metabolism , Rats , Stimulation, ChemicalABSTRACT
1. The rates of aniline metabolism have been studied in vitro using rat liver homogenates, and in vivo by determination of the unchanged aniline remaining in the cadaver. 2. Metabolism of aniline in vivo is stimulated by phenobarbital and 3,4-benzpyrene, and inhibited by SKF 525-A. 3. Cyclobarbital and phenacetin stimulate aniline metabolism both in vitro and in vivo. 4. Pre-treatment with aniline impaired the metabolism of aniline in vivo but increased the in vitro metabolism to p-aminophenol. Pre-treatment of rats with phenobarbital and aniline did not accelerate metabolism of aniline in vivo but the stimulating effect of phenobarbital on protein synthesis in microsomes was maintained. In contrast, pre-treatment with 3,4-benzpyrene and aniline stimulated metabolism of aniline in vivo. The possible mechanism of changes in aniline metabolism due to previous exposure to aniline is discussed.
Subject(s)
Aniline Compounds/metabolism , Liver/metabolism , Aniline Hydroxylase/metabolism , Animals , Barbiturates/pharmacology , Benzopyrenes/pharmacology , Kinetics , Liver/drug effects , Male , Microsomes/drug effects , Microsomes, Liver/metabolism , Phenacetin/pharmacology , Phenobarbital/pharmacology , Proadifen/pharmacology , Rats , Time FactorsABSTRACT
Exposure of rats to aniline at daily doses of 50 mg/kg of body weight over a month stimulated the microsomal metabolism as manifested by (1) acceleration of p-hydroxylation of anilin and N-demethylation of aminopyrine in 9-000 times g postmitochondrial supernatant of the liver, (2) shortening the sleeping time after hexobarbital, and (3) reduction of the antipyretic effect of phenacetin. In the rats exposed to nitrobenzene in a similar manner to aniline, nitroreduction of nitrobenzene and p-hydroxylation of aniline remained unaffected; the antipyretic effect of phenacetin was decreased, whereas hexobarbital sleeping time remained unchanged. Exposure of rats to benzene (50 mg/kg of body weight daily for a month) had no effect on the rate of hydroxylation of benzene and N-demethylation of aminopyrine. In benzene-exposed rats hexobarbital sleeping time was prolonged whereas the antipyretic effect of phenacetin was unaffected. Microsomal metabolism of aniline, nitrobenzene, and benzene was stimulated and inhibited when the rats were pretreated with phenobarbital and SKF 525-A, respectively.
