The induction and competitive inhibition of a high affinity microsomal nitrosodimethylamine demethylase by ethanol

Publisher Website
Google Scholar
Abstract
The effects of ethanol on the metabolism of nitrosamines by rat liver microsomes have been studied. Treatment of rats with 10 or 15% ethanol in drinking water for 3 days causes a 4- to 5-fold enhancement in microsomal N-nitrosodimethylamine demethylase (NDMAd) activity and a 40–60% increase in gross P-450 content. The enhancement is mainly due to the induction of a low Km form ( Km = 0.07 mM) of NDMAd. The treatment induces protein species with molecular weights between 50 000 and 52 000, some of which are believed to be P-450 isozymes with high affinity to NDMA. In addition to NDMA, treatment with ethanol also enhances the metabolism of N-nitroso-N-methylethylamine, N-nitrosomethylamline, and N-nitroso-N-methylbenzylamine. When added to the incubation mixture, ethanol and its homologs inhibit the demethylation of these nitrosamines by microsomes. Ethanol is a competitive inhibitor of the low Km NDMAd with a Ki of 0.31 mM and is less effective in inhibiting the metabolism of more lipophilic nitrosamines.