Doxorubicin and epirubicin iron-induced generation of free radicals in vitro. A comparative study

To ascertain any differences in myocardial injury exerted by the anthracyclines doxorubicin and epirubicin, their ability to generate oxygen free radicals when mixed with Fe(II) was examined in vitro using an oxygen electrode. 5-250 micrograms/ml doxorubicin or epirubicin consumed oxygen when mixed with 50 or 100 mumol/l Fe(II). Addition of 75 mumol/l cytochrome C showed that of the consumed oxygen, approximately 80% entered the monovalent pathway of oxygen reduction. The strong inhibitory effect of 250 mg/l catalase indicates that most of the superoxide radicals generated are further reduced to hydrogen peroxide by both anthracyclines. Addition of metal chelators DTPA (100 mumol/l), or DDTC (50 mumol/l) did not affect oxygen consumption, whereas EDTA (100 mumol/l) or desferrioxamine (100 mumol/l) with anthracyclines and Fe(II) rather stimulated oxygen consumption. It is concluded that there are no significant differences in the amount or proportion of generated oxygen free radicals between doxorubicin and epirubicin when mixed with Fe(II) in a cell-free system in vitro. Thus, the ability of the anthracyclines, in conjunction with iron alone, to generate radicals does not explain the differences of the drugs in causing myocardial injury.