The induction and competitive inhibition of a high affinity microsomal nitrosodimethylamine demethylase by ethanol.
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 50000 and 52000, 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-nitrosomethylaniline, 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.
D000818:Animals; D001667:Binding, Competitive; D019392:Cytochrome P-450 CYP2E1; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D000431:Ethanol / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D051381:Rats; D011919:Rats, Inbred Strains; D013379:Substrate Specificity
D000431:Ethanol; D003577:Cytochrome P-450 Enzyme System; D019392:Cytochrome P-450 CYP2E1; D010089:Oxidoreductases, N-Demethylating