A 50-year-old man with breast cancer is prescribed doxorubicin. He develops dose-dependent dilated cardiomyopathy after completing his regimen. The primary mechanism of doxorubicin cardiotoxicity is:

• A Formation of doxorubicin-iron complexes generating reactive oxygen species ✓
• B Direct inhibition of myocardial beta-1 adrenergic receptors
• C Inhibition of topoisomerase II in cardiac mitochondrial DNA
• D Depletion of cardiac glutathione by alkylation

Explanation

Doxorubicin undergoes redox cycling and forms complexes with iron (Fe2+/Fe3+), generating free radicals (particularly hydroxyl radicals via the Fenton reaction) that cause oxidative damage to cardiomyocytes, which have relatively low catalase activity. Cardiac cells are particularly vulnerable because they have high metabolic demands and limited antioxidant defenses. Dexrazoxane, an iron-chelating agent, is used to prevent anthracycline cardiotoxicity by competitively binding iron.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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