Trace transition metal-catalyzed reactions in the microsomal metabolism of alkyl hydrazines to carbon-centered free radicals.
Radical production from alkyl hydrazines (i.e. phenelzine and benzylhydrazine) in rat liver microsomes has been proposed to occur via cytochrome P-450-catalyzed one-electron oxidation followed by beta-scission of an alkyl radical. In microsomes treated with phenelzine (2-phenylethylhydrazine), NADPH, and the spin trap alpha-(4-pyridyl 1-oxide)-N-tert-butylnitrone (4-POBN), the 4-POBN/2-phenylethyl radical adduct was detected by electron paramagnetic resonance spectroscopy. The addition of catalase and superoxide dismutase resulted in a 28.5 and 24% decrease in radical production, respectively. The concentration of the 4-POBN/2-phenylethyl radical adduct decreased significantly in the presence of metal chelators, i.e. EDTA, diethylenetriaminepentaacetic acid (DTPA), or deferoxamine mesylate. When phenelzine was incubated with deferoxamine mesylate-washed microsomes and NADPH in Chelex-treated incubation buffer, no significant radical adduct formation was detected. Addition of iron-chelator complexes (either Fe(3+)-DTPA or Fe(3+)-EDTA) greatly stimulated production of the 4-POBN/2-phenylethyl radical adduct in this system. These results show that the 2-phenylethyl radical produced from phenelzine in a microsomal system arises via a trace transition metal-catalyzed reaction. This reaction may occur through oxidation of phenelzine by the hydroxyl radical, which has also been spin-trapped with 4-POBN in this system.
Rumyantseva
G V
GV
National Institute of Environmental Health Sciences, National Institutes of Health, Laboratory of Molecular Biophysics, Research Triangle Park, North Carolina 27709.
Kennedy
C H
CH
Mason
R P
RP
D000818:Animals; D002374:Catalase / Q000378:metabolism / Q000494:pharmacology; D002614:Chelating Agents / Q000494:pharmacology; D003676:Deferoxamine / Q000494:pharmacology; D004578:Electron Spin Resonance Spectroscopy / Q000379:methods; D005609:Free Radicals; D006834:Hydrazines / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D009589:Nitrogen Oxides; D010624:Phenelzine / Q000378:metabolism; D011725:Pyridines; D051381:Rats; D011919:Rats, Inbred Strains; D013113:Spin Labels; D013329:Structure-Activity Relationship; D013482:Superoxide Dismutase / Q000378:metabolism / Q000494:pharmacology
D002614:Chelating Agents; D005609:Free Radicals; D006834:Hydrazines; D009589:Nitrogen Oxides; D011725:Pyridines; D013113:Spin Labels; C043438:alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone; D002374:Catalase; D013482:Superoxide Dismutase; D003676:Deferoxamine; D010624:Phenelzine