Oxidative metabolism of some hydrazine derivatives by rat liver and lung tissue fractions.
The enzyme systems in rat liver and lung responsible for the oxidative metabolism of hydrazine derivatives were studied to determine whether these enzymes, cytochrome P-450 and monoamine oxidase, were responsible for metabolically activating hydrazines to carcinogenic/toxic metabolites. Cytochrome P-450 preferentially oxidized the nitrogen to nitrogen bond of 1,2-disubstituted hydrazines and hydrazides, while monoamine oxidase oxidized the nitrogen to nitrogen bond of all the classes of hydrazine derivatives that were tested. Oxidation of the nitrogen to nitrogen bond led to the formation of stable azo intermediates in the case of 1,2-disubstituted hydrazines and to unstable monoazo (diazene) metabolites in the case of monosubstituted hydrazines and hydrazides. In addition, cytochrome P-450 preferentially oxidized the carbon to nitrogen bond of monoalkylhydrazines; this reaction resulted in the formation of aldehyde metabolites (via hydrazone intermediates). Monosubstituted hydrazines were shown to be potent, irreversible inhibitors of mitochondrial monoamine oxidase. In contrast, the 1,2-disubstituted hydrazines appeared to be good substrates for the monoamine oxidase and served as competitive inhibitors at high concentrations. There did not appear to be any monoamine oxidase isozyme (form A or B) specificity in the metabolism of either the 1,2-disubstituted hydrazines or the monoalkylhydrazines, ethyl- and n-propylhydrazine.
Erikson
J M
JM
Department of Biochemistry, University of Texas Health Science Center, Dallas.
Prough
R A
RA
D019813:1,2-Dimethylhydrazine; D000818:Animals; D003010:Clorgyline / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004127:Dimethylhydrazines / Q000378:metabolism; D006834:Hydrazines / Q000378:metabolism*; D007490:Iproniazid / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008168:Lung / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D008930:Mitochondria, Liver / Q000201:enzymology / Q000378:metabolism; D008995:Monoamine Oxidase / Q000378:metabolism; D010084:Oxidation-Reduction; D010293:Pargyline / Q000031:analogs & derivatives / Q000494:pharmacology; D011344:Procarbazine / Q000378:metabolism; D011437:Propylamines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D004127:Dimethylhydrazines; D006834:Hydrazines; D011437:Propylamines; C009054:propargylamine; C029424:hydrazine; D011344:Procarbazine; D003577:Cytochrome P-450 Enzyme System; D010293:Pargyline; D007490:Iproniazid; D008995:Monoamine Oxidase; D019813:1,2-Dimethylhydrazine; D003010:Clorgyline