The nature of microsomal N-nitrosodimethylamine demethylase and its role in carcinogen activation.
The subcellular localization of N-nitrosodimethylamine (NDMA) demethylase in rat liver cells and the role of this enzyme in the activation of NDMA were studied. The enzyme activity was predominantly located in the microsomal fraction and the addition of cytosol to the microsomes did not produce a synergistic effect. The microsomal NDMA demethylase activity appeared to correspond to the ability of the microsomes to convert NDMA to the alkylating species. The alkylation of DNA was assayed by the measurement of O6-methylguanine and 7-methylguanine by fluorescence after isolation by h.p.l.c. The induction of microsomal NDMA demethylase activity by isopropanol, ethanol, acetone, and fasting was closely related to the increase of DNA methylation by NDMA in an incubation system in vitro. Pretreatment of rats with ethanol, which induced hepatic NDMA demethylase activity, enhanced DNA alkylation in vivo with a high dose of NDMA (75 mg/kg body weight) but not with low doses of NDMA (less than or equal to 25 mg/kg body weight). The role of NDMA demethylase in the activation of NDMA is discussed.
D000818:Animals; D001711:Biotransformation; D019392:Cytochrome P-450 CYP2E1; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004128:Dimethylnitrosamine / Q000378:metabolism / Q000494:pharmacology; D004790:Enzyme Induction; D000431:Ethanol / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D008745:Methylation; D008862:Microsomes, Liver / Q000201:enzymology*; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains
D000431:Ethanol; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D019392:Cytochrome P-450 CYP2E1; D010089:Oxidoreductases, N-Demethylating; D009251:NADPH-Ferrihemoprotein Reductase; D004128:Dimethylnitrosamine