The Adriamycin (doxorubicin)-induced inactivation of cytochrome c oxidase depends on the presence of iron or copper.
1. It was confirmed that Adriamycin (doxorubicin) inactivates cytochrome c oxidase upon incubation. However, further investigation shows that this inactivation is strongly dependent upon the presence of Fe3+ and Cu2+. Trace amounts of these transition metal ions, present in phosphate and Tris buffers, bind strongly to the Adriamycin and the complex formed is responsible for the inactivation of cytochrome c oxidase. No Adriamycin-induced inactivation of cytochrome c oxidase occurred in the presence of EDTA or in phosphate buffers purified on a cation exchange column to remove trace metals. 2. The metal ion-induced inactivation of cytochrome c oxidase by Adriamycin results in significant decreases in both the maximum velocity and the Michaelis constant. The degree of inactivation is strongly dependent on the Fe3+ concentration. 3. Cardiolipin partially protects against cytochrome c oxidase inactivation, presumably by binding to the cytochrome c oxidase, whereas catalase or superoxide dismutase partially protect by scavenging damaging reactive oxygen species generated within a Fe3+-Adriamycin-enzyme complex.
Hasinoff
B B
BB
Memorial University of Newfoundland, St. John's, Canada.
Davey
J P
JP
O'Brien
P J
PJ
D000818:Animals; D001667:Binding, Competitive; D002308:Cardiolipins / Q000494:pharmacology; D002417:Cattle; D003300:Copper / Q000494:pharmacology*; D003574:Cytochrome c Group / Q000494:pharmacology; D004229:Dithiothreitol / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology*; D004533:Egtazic Acid / Q000494:pharmacology; D003576:Electron Transport Complex IV / Q000037:antagonists & inhibitors*; D004789:Enzyme Activation / Q000187:drug effects; D004794:Enzyme Repression / Q000187:drug effects; D005978:Glutathione / Q000494:pharmacology; D007501:Iron / Q000494:pharmacology*; D007700:Kinetics
D002308:Cardiolipins; D003574:Cytochrome c Group; D004533:Egtazic Acid; D003300:Copper; D004317:Doxorubicin; D007501:Iron; D003576:Electron Transport Complex IV; D005978:Glutathione; D004229:Dithiothreitol