Immunochemical studies on the metabolism of nitrosamines by ethanol-inducible cytochrome P-450.
The ethanol-induced rabbit liver microsomal cytochrome P-450, P-450LM3a, has been shown previously to efficiently catalyze the demethylation of N-nitrosodimethylamine (NDMA) with a Km of 2.9 mM. Since the predominant Km in hepatic microsomes from ethanol-treated rabbits is 0.07 mM, the role of P-450LM3a in the activation of this carcinogen has been uncertain. In the present study, antibodies to P-450LM3a were shown to almost completely inhibit NDMA demethylation by the purified P-450 in a reconstituted system as well as the low-Km activity of liver microsomes from control or ethanol-treated rabbits. In contrast, the antibody did not inhibit the high-Km NDMA demethylase activity in the microsomes. These results indicate that P-450LM3a is the major P-450 responsible for the low-Km NDMA demethylase activity. In addition, evidence is provided for the existence of a cytochrome immunochemically similar to P-450LM3a in liver microsomes from rats, mice, and guinea pigs that effectively catalyzes the demethylation of NDMA.
D000818:Animals; D000906:Antibodies; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000276:immunology; D004128:Dimethylnitrosamine / Q000378:metabolism*; D004790:Enzyme Induction; D000431:Ethanol / Q000494:pharmacology*; D006168:Guinea Pigs; D007700:Kinetics; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D011817:Rabbits; D051381:Rats
D000906:Antibodies; D000431:Ethanol; D003577:Cytochrome P-450 Enzyme System; D004128:Dimethylnitrosamine