Effects of cytochrome P-448 and P-450 inducers on microsomal dimethylnitrosamine demethylase activity and the capacity of isolated microsomes to activate dimethylnitrosamine to a mutagen

Abstract

The relationship between microsomal dimethylnitrosamine (DMN) demethylase activity and the capacity of isolated hepatic microsomes to activate DMN to a mutagen was examined using microsomes from C57 and DBA/2 mice which had been exposed to three different types of microsomal enzyme inducers: phenobarbital, which induces cytochrome P-450, 3-methylcholanthrene, which induces cytochrome P-448, and the polychlorinated biphenyl, Aroclor 1254 which appears to induce both types of cytochromes. DMN induced mutagenesis was assayed by a Salmonella auxotroph reversion test. With the C57 mice all three inducers increased both the activity of microsomal DMN demethylase and the capacity of the microsomes to activate DMN mutagenicity. In each case, however, the increase in mutagenicity was disproportionately greater than the increase in DMN demethylase activity. This was particularly evident with microsomes prepared from Aroclor induced mice. Microsomes from 3-methylcholanthrene treated DBA/2 mice were not induced for DMN demethylase or the activation of DMN mutagenicity. In addition the capacity of Aroclor to function as an inducer was relatively poor in this strain. Both DMN demethylation and mutagenesis were inhibited by the addition of either SKF 525-A or benzo(a)pyrene to the reaction mixtures. Thus microsomal activation of DMN to a mutagen and DMN demethylase appear to involve both cytochromes P-450 and P-448.