Key result
Adriamycin inactivates cytochrome c oxidase by forming complexes with Fe3+ and Cu2+ transition metals.
Why the study?
The mechanism by which Adriamycin inactivates cytochrome c oxidase and the role of trace metal ions in this process were not fully understood.
Does Adriamycin-induced inactivation of cytochrome c oxidase depend on the presence of transition metal ions?
Does Adriamycin-induced inactivation of cytochrome c oxidase depend on the presence of transition metal ions?
Doxorubicin-induced inactivation of cytochrome c oxidase is mediated by a metal-ion complex (Fe3+ or Cu2+) generating reactive oxygen species, providing mechanistic insight into its cellular toxicity.
Answers are grounded in this paper and cite their sources.
May guide metal-chelator strategies against doxorubicin toxicity; leaves open clinical translation from animal data.
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.
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Hasinoff et al. (1989) studied this question. Adriamycin (doxorubicin) with Fe3+ or Cu2+ vs. Adriamycin without trace metals (with EDTA or purified buffer) was evaluated on Inactivation of cytochrome c oxidase. Adriamycin-induced inactivation of cytochrome c oxidase is strongly dependent on the presence of Fe3+ and Cu2+ transition metal ions, which form a complex with the drug.
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