The oxidation of hydrazine derivatives catalyzed by the purified liver microsomal FAD-containing monooxygenase.

A number of hydrazine derivatives were tested as substrates for the purified liver microsomal FAD-containing monooxygenase and the kinetic properties of the oxidation reactions were partially characterized. Only 1,l-dimethylhydrazine, l-methyl-l-phenylhydrazine, and the N-aminoheterocyclic hydrazines are oxidized as effectively as N,N-dimethylaniline, one of the best N-methylamine substrates for the enzyme. In addition, the pH-rate profiles for the oxidation of several hydrazines were identical with that noted for N,N-dimethylaniline. Studies aimed at defining the stoichiometry of the monooxygenase-catalyzed hydrazine oxidation have indicated that the oxidation reaction is stoichiometric (1:l:l) with regard to NADPH, oxygen, and either 1,l-dimethylhydrazine or l-methyl-l-phenylhydrazine as substrate. However, the oxidation of the N-aminoheterocyclic hydrazines required two molecules each of NADPH and oxygen to metabolize one molecule of N-aminopiperidine or N-aminohomopiperidine. The formation and stoichiometry of the products obtained from 1,l-dimethylhydrazine strongly support the existence of a diazene intermediate that may result from the dehydration of an N-hydroxy metabolite which can tautomerize subsequently under certain conditions to yield a formaldehyde methylhydrazone (possibly via an azomethinimine species). Inhibitors of the cytochrome P-460-dependent monooxygenase were without effect on the microsomal Ndemethylation of 1,l-dimethylhydrazine, but methimazole, a substrate for the FAD-containing monooxygenase, strongly inhibited the reaction catalyzed by rat and hamster liver microsomes. This microsomal activity was not induced by animal pretreatment with phenobarbital or 3-methylcholanthrene. These results strongly suggest that the microsomal metabolism of 1,l-dimethylhydrazine, and perhaps other 1,l-disubstituted hydrazines, is principally catalyzed by the PADcontaining monooxygenase.