The iron(III)-adriamycin complex inhibits cytochrome c oxidase before its inactivation

Abstract

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.

Copper-Dependent Inhibition of Human CytochromecOxidase by a Dimeric Conformer of Amyloid-β1-42

“…It may facilitate A␤ oligomerization (Atwood et al, 1998;Klug et al, 2003), may facilitate the formation of specific A␤ conformers such as dityrosine A␤ (Galeazzi et al, 1999;Curtain et al, 2001;Atwood et al, 2004), or may facilitate A␤-COX interaction, serving as a ligand. A precedent for the latter scenario may be the adriamycin/Fe 3ϩ -mediated inhibition of COX observed by Hasinoff and Davey (1988). These authors found that adriamycin inhibited COX with an inhibition constant of 12 M when in the presence of Fe 3ϩ , and this inhibition was lost when the metal was removed by chelators.…”

Ameliorative effect of naringin against doxorubicin-induced acute cardiac toxicity in rats

“…There is evidence suggesting that the Dox treatment can induce apoptosis by multiple different mechanisms (Mukhopadhyay et al, 2009). Moreover, Dox causes iron dysregulation by the formation of Fe 3+ -Dox complex leading to inactivation of cytochrome c oxidase (Hasinoff & Davey, 1988), and changes in iron homeostatic processes associated with aconitase-iron regulatory protein-1 (ACO1) (Minotti et al, 1998).…”

The inhibition of a membrane-bound enzyme as a model for anaesthetic action and drug toxicity

“…Galactosylsphingosine as well was observed (Igisu & Nakamura, 1986) to inhibit cytochrome c oxidase strongly (Ki -5 tM). In previous studies cytochrome c oxidase kinetics exhibited weak inhibition by pentan-I -ol, propan-1 -ol, propan-2-ol, methanol, glycerol and sucrose (Hasinoff & Davey, 1987, 1988. It has been shown by Orii & Yoshikawa (1973) that hydroxylamine, hydrazine, semicarbazide, salicylaldoxime and ethylxanthate inhibit cytochrome c oxidase with inhibition constants as low as 0.5 ,uM.…”