Organ-specific effects of the carcinogen methylazoxymethanol related to metabolism by nicotinamide adenine dinucleotide-dependent dehydrogenases

D. J. Grab, M. S. Zedeck

Research output: Contribution to journalArticle

Abstract

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 has been suggested that methylazoxymethanol might be converted by alcohol dehydrogenase to a reactive aldehydic form. The enzyme activity dependent on nicotinamide adenine dinucleotide (NAD+) and nicotinamide adenine dinucleotide phosphate was determined in 169,000 x g supernatants from tissues sensitive or 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 CA1-2) activity when either ethanol or methylazoxymethanol was used. In some tissues NAD 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.

Original languageEnglish (US)
Pages (from-to)4182-4189
Number of pages8
JournalCancer Research
Volume37
Issue number11
StatePublished - 1977
Externally publishedYes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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