Free radical production from normal and adriamycin-treated rat cardiac sarcosomes.
The production of hydroxyl radicals in rat myocardial sarcosomes treated with adriamycin was demonstrated by the electron spin resonance technique of spin trapping. Using the spin trapping agent 5,5-dimethyl-1-pyrroline-N-oxide (DMPO), the formation of a hydroxyl radical spin adduct was observed in adriamycin-treated rat heart sarcosomes with NADPH as co-factor. Oxygen, NADPH and sarcosomal protein were absolute requirements for hydroxyl radical production. Hydroxyl radical spin adduct formation was not inhibited by the metal ion chelators diethylenetriaminepenta-acetic acid (DETAPAC) or desferrioxamine, or by addition of superoxide dismutase but could be inhibited by addition of catalase and high concentration of the hydroxyl radical scavengers mannitol and N-acetylcysteine. Hydroxyl radical production in adriamycin-treated rat myocardial sarcosomes appears to arise from the reductive metabolism of adriamycin by an NADPH-dependent quinone reductase--NADPH: cytochrome P450 reductase; the reduced quinone (semiquinone) reduces oxygen to hydrogen peroxide, probably via superoxide, although this was not detected. The hydrogen peroxide appears to react directly with adriamycin semiquinone, although involvement of traces of iron in a Fenton type of reaction cannot be excluded. From the observations it is suggested that adriamycin-induced cardiotoxicity is an oxidative pathology arising from intracellular generation of relatively high levels of hydroxyl radicals.
Thornalley
P J
PJ
Dodd
N J
NJ
D000818:Animals; D003497:Cyclic N-Oxides / Q000378:metabolism; D004317:Doxorubicin / Q000378:metabolism / Q000633:toxicity*; D004578:Electron Spin Resonance Spectroscopy; D006321:Heart / Q000187:drug effects*; D006878:Hydroxides; D017665:Hydroxyl Radical; D066298:In Vitro Techniques; D008297:Male; D008931:Mitochondria, Muscle / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D013481:Superoxides / Q000378:metabolism
D003497:Cyclic N-Oxides; D006878:Hydroxides; D013481:Superoxides; D017665:Hydroxyl Radical; C017245:5,5-dimethyl-1-pyrroline-1-oxide; D004317:Doxorubicin