Antioxidant defense against anthracycline cardiotoxicity by metallothionein

Anthracycline cardiotoxicity is related to oxidative stress generated from the metabolism of anthracyclines in the heart. Studies using transgenic mice with high levels of antioxidants such as catalase or metallothionein (MT) specifically in the heart have demonstrated that elevation of cardiac antioxidant defense leads to intervention of anthracycline cardiotoxicity. MT protection against anthracycline-induced cardiac toxicity is related to its antiapoptotic effect by inhibiting both p38-MAPK-mediated and mitochondrial cytochrome c-release-mediated apoptotic signaling. The anti-apoptotic effect of MT is closely related to its antioxidant action, which involves regulation of zinc homeostasis by the MT redox cycle. MT interferes with oxidant-mediated detrimental process through at least in part zinc release and zinc transfers directly from MT to acceptor proteins. In addition, MT posttranslationally modulates critical proteins involved in mitochondrial respiration and energy metabolism. All of these processes constitute the mechanisms by which MT protects from anthracycline cardiotoxicity.