Microsomal Drug-metabolizing Enzymes In Rat Research Articles

Effects of Methylsulfonyl Metabolites of PCBs Accumulated in Tissues of Mammals on Activities of Hepatic Microsomal Drug-Metabolizing Enzymes in Rats (Proceedings of the 19th Symposium on Toxicology and Environmental Health)

Effects of Methylsulfonyl Metabolites of PCBs Accumulated in Tissues of Mammals on Activities of Hepatic Microsomal Drug-Metabolizing Enzymes in Rats (Proceedings of the 19th Symposium on Toxicology and Environmental Health)

Evidence that methylsulfonyl metabolites of m-dichlorobenzene are causative substances of induction of hepatic microsomal drug-metabolizing enzymes by the parent compound in rats

This study was undertaken to clarify the relationship between the formation of 2,4- and 3,5-dichlorophenyl methyl sulfones, metabolites of m-dichlorobenzene (DCB), and their inducing effect on hepatic microsomal drug-metabolizing enzymes in rats. When m-DCB was injected ip into bile duct-cannulated rats, little or no methyl sulfones were detected in blood, liver, kidneys, adipose tissue, or bile. In the antibiotic-pretreated rats dosed with m-DCB, metabolite concentrations in the blood and the three tissues markedly decreased. These findings suggest that the formation of methylsulfonyl metabolites from m-DCB depends largely upon the metabolism of some precursor(s) excreted in the bile by intestinal microflora. The increasing effects of m-DCB administration on the activities of aminopyrine and aniline metabolizing enzymes and the contents of cytochromes P-450 and b 5 in hepatic microsomes were scarcely observed in the bile duct-cannulated and antibiotic-pretreated rats, in which the drug-metabolizing enzymes were able to be induced by phenobarbital treatment. On the other hand, in rats administered 2,4- or 3,5-dichlorophenyl methyl sulfone hepatic distribution of each methyl sulfone was similar to that in intact rats, and the degree of increase of the above four parameters was nearly the same as that in the intact rats. These findings provide evidence that the induction of drug-metabolizing enzymes by m-DCB is not due to the action of m-DCB but is due to its methylsulfonyl metabolites.

Induction of hepatic drug-metabolizing enzymes in rats, dogs, and monkeys after repeated administration of an anti-inflammatory hexahydroindazole.

The effect of repeated administration of an anti-inflammatory hexahydroindazole, (+/-)-3,3 alpha,4,5,6,7-hexahydro-2-[3-(4-morpholinyl)-propyl]-3-phenyl-7-(phenylmethylene)-2H-indazole (HMPPI), on hepatic microsomal drug-metabolizing enzymes in rats, dogs and monkeys was studied. Dose-dependent increases in the ratio of liver weight to body weight were observed in all three species. Microsomal protein concentration increased in rats and monkeys but not in dogs. Cytochrome P-450 concentration and aminopyrine N-demethylase activity increased in all species. Aniline hydroxylase activity increased only in dogs. In all three species, the largest increase in all parameters, except for the liver weight/body weight ratio, was observed in animals on the intermediate dose (50 mg/kg per d) of the hexahydroindazole, probably of the toxicity of the hexahydroindazole at the high dose (250 mg/kg per d).

92) - Effect of Habu venom on microsomal drug-metabolizing enzymes in rats (Report 3)

92) - Effect of Habu venom on microsomal drug-metabolizing enzymes in rats (Report 3)

Variation in the activity of liver microsomal drug-metabolizing enzymes in rats in relation to the age

The variation in the activity of the microsomal drug-metabolizing enzymes in rats in relation to age was studied. The systems used were the in-vitro metabolism of hexobarbital, pentobarbital, meprobamate, carisoprodol and strychnine, the in-vivo metabolism of pentobarbital, meprobamate and carisoprodol and the duration of pentobarbital hypnosis and carisoprodol paralysis and the toxicity of strychnine and OMPA (Octamethylpyrophosphoramide). New-born rats showed only a very low metabolic activity, but this increased progressively until 30 days after which it gradually decreased with aging. In the metabolisms in vitro, 30-day-old rats showed about 2.7, 2.2, 1.7 and 1.5 times higher activity than those of 250, 150, 100 and 60 days old, respectively. Similar, though smaller, differences were observed in vivo. The duration of pentobarbital hypnosis, carisoprodol paralysis and strychnine toxicity was almost the same in immature (30 days old) and adult rats (60–150 days old). Possibly, the immature have a higher sensitivity to the drugs than the adult rats, but this is overshadowed by the higher metabolic activity in the immature rats. The possible mechanism for the marked difference in the activity in vitro of the drug-metabolizing enzymes among the differently aged rats is discussed in connection with the variation of in-vivo metabolism and activity of microsomal TPNH oxidase.