[Free radicals mediate cardiac toxicity induced by adriamycin].
Anthracycline antibiotics, including adriamycin (ADM), are widely used to treat various human cancers, but their clinical use has been limited because of their cardiotoxicity. ADM is especially toxic to heart tissue. The mechanisms responsible for the cardiotoxic effect of ADM have been very/extremely controversial. This review focuses on the participation of free radicals generated by ADM in the cardiotoxic effect. ADM is reduced to a semiquinone radical species by microsomal NADPH-P450 reductase and mitochondrial NADH dehydrogenase. In the presence of oxygen, the reductive semiquinone radical species produces superoxide and hydroxyl radicals. Generally, lipid peroxidation proceeds by mediating the redox of iron. ADM extracts iron from ferritin to form ADM-Fe3+, which causes lipid peroxidation of membranes. These events may lead to disturbance of the membrane structure and dysfunction of mitochondria. However, superoxide dismutase and hydroxyl radical scavengers have little effect on lipid peroxidation induced by ADM-Fe3+. Alternatively, ADM is oxidatively activated by peroxidases to convert to an oxidative semiquinone radical, which participates in inactivation of mitochondrial enzymes or including succinate dehydrogenase and creatine kinase. Here, we discuss the activation of ADM and the role of reductive and oxidative ADM semiquinone radicals in the cardiotoxic effect of this antibiotic.
Hokkaido College of Pharmacy, 7-1 Katsuraoka-cho, Otaru 047-0264, Japan. muraokas@hokuyakudai.ac.jp
Sanae
S
Muraoka
Toshiaki
T
Miura
D000818:Animals; D018943:Anthracyclines / Q000378:metabolism / Q000633:toxicity*; D000903:Antibiotics, Antineoplastic / Q000378:metabolism / Q000633:toxicity*; D016227:Benzoquinones; D003402:Creatine Kinase / Q000378:metabolism; D005293:Ferritins / Q000378:metabolism; D005609:Free Radicals; D006321:Heart / Q000187:drug effects*; D006801:Humans; D017665:Hydroxyl Radical; D007501:Iron / Q000378:metabolism; D015227:Lipid Peroxidation; D008861:Microsomes / Q000201:enzymology; D008928:Mitochondria / Q000201:enzymology; D009245:NADH Dehydrogenase / Q000378:metabolism; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D013481:Superoxides
D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D016227:Benzoquinones; D005609:Free Radicals; D013481:Superoxides; C025232:semiquinone radicals; D017665:Hydroxyl Radical; D005293:Ferritins; D007501:Iron; D009251:NADPH-Ferrihemoprotein Reductase; D009245:NADH Dehydrogenase; D003402:Creatine Kinase