Studies on the metabolism of dimethylnitrosamine in the rat. II. The effects of phenobarbitone and 20-methylcholanthrene on the in vitro and in vivo metabolism and acute toxicity of dimethylnitrosamine in young and mature rats

Abstract

Following ip administration of 14C-labelled dimethylnitrosamine (DMN) to rats. 14CO 2 excretion was found to proceed approximately twice as fast in the young animal as in the mature rat of either sex. In contrast, the hepatic DMN demethylase activity and a number of biochemical parameters of the microsomal mixed-function oxidase system were similar in both age groups. Pretreatment with phenobarbitone or 20-methylcholanthrene increased hepatic DMN demethylase activity and other parameters of microsomal enzymes in both groups of rats, but did not alter the 14CO 2 excretion rates significantly in the intact animals, except in mature females. Neither did SKF 525-A. a microsomalenzyme inhibitor, affect this in vivo index of DMN metabolism. Parallel studies on aminopyrine revealed an in vitro and in vivo induction of metabolism in rats pretreated with phenobarbitone, while SKF 525-A markedly inhibited 14CO 2 excretion from [ 14C]aminopyrine administered to rats. Acute toxicity studies showed that whereas phenobarbitone afforded some protection in mature female rats but not in young males, 20-methylcholanthrene treatment rendered both groups more susceptible to DMN toxicity. These results are discussed in terms of the role of hepatic DMN demethylase in determining the in vivo metabolism and acute toxicity of DMN in the rat.