Free-radical formation by mitomycin C and its novel analogs in cardiac microsomes and the perfused rat heart.
Using a spin-trapping technique, we have examined free-radical formation by mitomycin C and its analogs, BMY 25282 and BMY 25067, in rat cardiac microsomes and isolated perfused rat hearts. All three drugs stimulated 2--4-fold OH radical formation in cardiac microsomes which was inhibited by SOD and catalase. Superoxide anion radical was also detected in the presence of diethylenetetraaminopentaacetic acid. Addition of DMSO yielded methyl radicals, thus indicating the production of free OH under these conditions. Similar stimulation of OH formation (2--3-fold) in the perfusates from rat hearts was detected with all three drugs. Perfusion with catalase (550 U/ml) completely suppressed the OH signal both in the presence and absence of the drugs, thus suggesting the intermediacy of hydrogen peroxide. However, BMY 25067-induced OH formation was more sensitive to inhibition by superoxide dismutase (SOD) and the iron chelator ICRF-187. Perfusion with DMSO produced methyl radicals at the expense of OH in the presence of all three drugs. SOD and catalase inhibited DMPO-OH signals, indicating that most of the OH formation was extracellular in this setting. While mitomycin C and BMY 25067 (up to 10 microM) did not affect the heart rate, perfusion with 10 microM BMY 25282 caused acute arrhythmia and cardiac standstill within 20 min. An initial surge in OH formation (2-fold) accompanied this cardiotoxic effect. Both the arrhythmia and the free radical signal were partially blocked by SOD, catalase and ICRF-187, indicating that iron-dependent oxygen radical formation from BMY-25282 (and possibly other compounds) is involved, in part, in inducing toxic manifestations in the rat heart and possibly in clinic.
Politi
P M
PM
Clinical Pharmacology Branch, National Cancer Institute, Bethesda, MD 20892.
Rajagopalan
S
S
Sinha
B K
BK
D000818:Animals; D002374:Catalase / Q000494:pharmacology; D004578:Electron Spin Resonance Spectroscopy; D005609:Free Radicals; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D006878:Hydroxides / Q000378:metabolism; D017665:Hydroxyl Radical; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism*; D016685:Mitomycin; D008937:Mitomycins / Q000494:pharmacology*; D009206:Myocardium / Q000378:metabolism*; D010477:Perfusion; D051381:Rats; D011919:Rats, Inbred Strains; D013481:Superoxides / Q000378:metabolism
D005609:Free Radicals; D006878:Hydroxides; D008937:Mitomycins; D013481:Superoxides; D017665:Hydroxyl Radical; D016685:Mitomycin; C046941:N(6)-((dimethylamino)methylene)mitomycin C; C055172:N-7-(2-(nitrophenyldithio)ethyl)mitomycin C; D002374:Catalase