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 anti-apoptotic 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.
Kang
Y James
YJ
University of Louisville School of Medicine, 511 S. Floyd St., MDR530, Louisville, KY 40202, USA. yjkang01@louisville.edu
D000818:Animals; D018943:Anthracyclines / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D000903:Antibiotics, Antineoplastic / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D000975:Antioxidants / Q000494:pharmacology* / Q000502:physiology*; D002316:Cardiotonic Agents; D006331:Heart Diseases / Q000139:chemically induced* / Q000517:prevention & control*; D006801:Humans; D008668:Metallothionein / Q000494:pharmacology* / Q000502:physiology*; D010084:Oxidation-Reduction; D011499:Protein Processing, Post-Translational / Q000502:physiology; D015032:Zinc / Q000378:metabolism
D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D000975:Antioxidants; D002316:Cardiotonic Agents; D008668:Metallothionein; D015032:Zinc