Organ-specific Effects of the Carcinogen Methylazoxymethanol Related to Metabolism by Nicotinamide Adenine Dinucleotide-dependent Dehydrogenases

Methylazoxymethanol acetate selectively induces a high incidence of tumors in rat liver and colon after a single treatment. The mechanism for this organotropism is unclear, especially since methylazoxymethanol spontaneously decomposes to a reactive alkylating agent. It had been suggested that methylazoxymethanol might be converted by alcohol dehydrogenase to a reactive aldehydic form. We determined enzyme activity dependent on nicotinamide adenine dinucleotide (NAD⁺) and nicotinamide adenine dinucleotide phosphate in 169, 000 x g supernatants from tissues sensitive and resistant to methylazoxymethanol. Liver fractions were most active in changing NAD⁺to its reduced form with methylazoxymethanol as substrate; colon and cecum were also active. Jejunum and ileum, resistant to the acute and chronic effects of methylazoxymethanol, showed little NAD+ dependent dehydrogenase activity when either ethanol or methylazoxymethanol was used. In some tissues, nicotinamide adenine dinucleotide phosphate was changed to its reduced form in the presence of methylazoxymethanol. The 35 to 75% ammonium sulfate pellet of liver 169, 000 x g supernatant was fractionated by gel filtration. Methylazoxymethanol NAD+ dependent activity coincided with alcohol dehydrogenase activity, suggesting that methylazoxymethanol is enzymatically acted on by an alcohol dehydrogenase-like enzyme. Pyrazole, an inhibitor of alcohol dehydrogenase, blocked NAD⁺reduction in the presence of methylazoxymethanol. In addition, methylazoxymethanol was a substrate for purified horse liver alcohol dehydrogenase. Pyrazole given to rats 2 hr prior to carcinogen prevented methylazoxymethanol-induced lethality. The data suggest that NAD+ dependent enzymatic reactions in tissue cytosol may, in part, be responsible for the organ-specific effects of methylazoxymethanol in the rat.