The iron(III)-adriamycin complex inhibits cytochrome c oxidase before its inactivation.
Cytochrome c oxidase was found to be competitively inhibited by a complex formed between Fe3+ and the cardiotoxic antitumour drug adriamycin (doxorubicin) with an inhibition constant, Ki, of 12 microM. This competitive inhibition precedes the slower Fe3+-adriamycin induced inactivation of cytochrome c oxidase. In strong contrast with this result, free adriamycin was not observed to either inhibit or inactivate cytochrome c oxidase (Ki greater than 3 mM). Since, typically, polycations are known to inhibit cytochrome c oxidase, the competitive inhibition displayed by the Fe3+-adriamycin complex may also result from its polycationic character. Cytochrome c oxidase was also inhibited by pentan-1-ol (Ki 13 mM), and kinetic studies carried out in the presence of both inhibitors demonstrated that the Fe3+-adriamycin complex and pentan-1-ol are mutually exclusive inhibitors of cytochrome c oxidase. The inhibitor pentan-1-ol was also effective in preventing the slow inactivation of cytochrome c oxidase induced by Fe3+-adriamycin, presumably by blocking its binding to the enzyme. It is postulated that the slow inactivation of cytochrome c oxidase occurs when reactive radical species are produced while the Fe3+-adriamycin is complexed to cytochrome c oxidase in an enzyme-inhibitor complex. The Fe3+-adriamycin-induced inactivation of cytochrome c oxidase may be, in part, responsible for the cardiotoxicity of adriamycin.
Hasinoff
B B
BB
Department of Chemistry, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Canada.
Davey
J P
JP
D000818:Animals; D001667:Binding, Competitive; D002417:Cattle; D004317:Doxorubicin / Q000494:pharmacology*; D003576:Electron Transport Complex IV / Q000037:antagonists & inhibitors*; D066298:In Vitro Techniques; D007501:Iron / Q000494:pharmacology*; D007700:Kinetics; D046911:Macromolecular Substances; D009206:Myocardium / Q000201:enzymology; D010084:Oxidation-Reduction; D000439:Pentanols / Q000494:pharmacology
D046911:Macromolecular Substances; D000439:Pentanols; D004317:Doxorubicin; D007501:Iron; D003576:Electron Transport Complex IV; C024999:n-pentanol