The oxidative demethylation of certain N-methylhydrazines by microsomal liver enzymes Public Deposited

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  • The presence in rat liver microsomes of an enzyme system which demethylates N-methylhydrazines and azo compounds to formaldehyde has been reported. Some of the compounds found to be substrates were monomethylhydrazine, N-isopropyl-α-(2-methylhydrazino)- p-toluamide and the azo derivative of the latter hydrazine. This enzyme can be classified as a mixed function oxidase as defined by Mason (Adv. in Enzymology 19:79,1957) since the N-demethylase was dependent upon the presence of a NADPH-regenerating system and molecular oxygen. The reaction was not inhibited by SKF 525-A (2-diethylaminoethyl diphenylpropyl acetate), a compound that has been found to inhibit many microsomal enzyme systems. The N-demethylase was inducible by both phenobarbital and 3-methylcholanthrene. Addition of carbon monoxide to microsomes and the treatment of microsomes with trypsin led to the conclusion that rat liver microsomes possess a phenobarbital-inducible N-demethylase dependent upon P-450 and a non-inducible N-demethylase independent of P-450. A mechanism was proposed for the demethylation of the Nmethylhydrazines. Since the azo derivatives of two of the hydrazines were oxidized at a greater rate than their parent compounds, it was postulated that the hydrazines are first oxidized to their azo derivatives which in turn are demethylated to formaldehyde by microsomes. The possible formation of an azoxy intermediate was discussed. An attempt was made to solubilize and purify the N-demethylase but without success.
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