Disposition and metabolism of the carcinogen reduced Michler's ketone in rats.
Studies on the in vivo and in vitro disposition of 4,4'-[14C]-methylenebis(N,N-dimethyl)benzamine (reduced Michler's ketone, RMK) were performed. Osborne-Mendel rats retained, after 24 hr, 78% of a p.o. dose of [14C]RMK. At 24 hr after an i.p. dose, fat, liver, and intestine represented major sites for deposition of radioactivity. The major urinary metabolite of RMK, representing 36% of the total radioactivity recovered in the urine, was N,N'-diacetyl-4,4'-(hydroxymethylene)dianiline. In vitro microsomal metabolism of RMK involved demethylation. Products included N,N-dimethyl-4,4'-methylenedianiline, N,N'-dimethyl-4,4'-methylenedianiline, N-methyl-4,4'-methylenedianiline, and 4,4'-methylenedianiline, representing 44.7, 5.3, 11.8, and 6.9%, respectively, of the total radioactivity recovered from the reaction mixture. Although none of the microsomal metabolites was a direct-acting mutagen in the standard Salmonella typhimurium assay, all could be activated to mutagens when incubated with 9000 X g liver supernatants and reduced nicotinamide adenine dinucleotide phosphate. The activation of 4,4'-methylenedianiline to a mutagen suggests that the methyl groups of RMK are not required for the conversion of RMK to a reactive electrophile.
D000273:Adipose Tissue / Q000378:metabolism*; D000814:Aniline Compounds / Q000378:metabolism*; D000818:Animals; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism; D009153:Mutagens; D051381:Rats; D014018:Tissue Distribution; D001559:Benzhydryl Compounds
D000814:Aniline Compounds; D002273:Carcinogens; D009153:Mutagens; C035475:N,N-dimethyl-4,4'-methylenedianiline; D001559:Benzhydryl Compounds; C035474:N-methyl-4,4'-methylenedianiline; C035473:N,N'-diacetyl-4,4'-hydroxymethylenedianiline; C035472:N,N,N',N'-tetramethyl-4,4'-methylenedianiline