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Disposition and Metabolism of the Carcinogen Reduced Michler's Ketone in Rats¹

Kettering-Meyer Laboratory, Southern Research Institute, Birmingham, Alabama 35255

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.

¹ This work was supported by Contract N01-CP-55721, Division of Cancer Cause and Prevention, National Cancer Institute, NIH, Department of Health, Education and Welfare.

² To whom requests for reprints should be addressed.

Received 2/ 1/82. Accepted 5/18/82.