The mitochondrial metabolism of 1,2-disubstituted hydrazines, procarbazine and 1,2-dimethylhydrazine.

Sonication of isolated rat hepatocytes caused a pronounced decrease in the metabolism of biphenyl due to dilution of the cytosolic pool of NADPH, but did not greatly reduce the rate of procarbazine oxidation to its azo derivative. This result suggested the existence of two enzyme systems which can oxidize 1,2-disubstituted hydrazines: an NADPH-dependent (cytochrome P-450) and an NADPH-independent hydrazine oxidase. Upon assaying the various cell fractions of the hepatocyte, it was noted that the NADPH-independent hydrazine oxidase activity was localized in the mitochondria. The reaction was not linked to mitochondrial electron transport, but preincubation of isolated mitochondria with N,N-dimethylpropargylamine markedly inhibited both monoamine oxidase activity (benzylamine and kynuramine deamination) and procarbazine oxidation. During a 15-fold purification of the enzyme, benzylamine oxidase and procarbazine oxidase activity copurified, demonstrating that the rat liver mitochondrial monoamine oxidase can convert procarbazine to its respective azo derivative. 1,2-Dimethyl- and monomethylhydrazine were also metabolized by monoamine oxidase. Procarbazine did not inactivate monoamine oxidase like other hydrazines; this most likely reflects the fact that the oxidation product of the 1,2-disubstituted hydrazines is a stable azo derivative. However, procarbazine is a competitive substrate for the enzyme and may exert some of its toxic neurological effects by altering the metabolism of biogenic amines.(ABSTRACT TRUNCATED AT 250 WORDS)