Inactivation of mitochondrial succinate dehydrogenase by adriamycin activated by horseradish peroxidase and hydrogen peroxide.
Although human cancers are widely treated with anthracycline drugs, these drugs have limited use because they are cardiotoxic. To clarify the cardiotoxic action of the anthracycline drug adriamycin (ADM), the inhibitory effect on succinate dehydrogenase (SDH) by ADM and other anthracyclines was examined by using pig heart submitochondrial particles. ADM rapidly inactivated mitochondrial SDH during its interaction with horseradish peroxidase (HRP) in the presence of H(2)O(2) (HRP-H(2)O(2)). Butylated hydroxytoluene, iron-chelators, superoxide dismutase, mannitol and dimethylsulfoxide did not block the inactivation of SDH, indicating that lipid-derived radicals, iron-oxygen complexes, superoxide and hydroxyl radicals do not participate in SDH inactivation. Reduced glutathione was extremely efficient in blocking the enzyme inactivation, suggesting that the SH group in enzyme is very sensible to ADM activated by HRP-H(2)O(2). Under anaerobic conditions, ADM with HRP-H(2)O(2) caused inactivation of SDH, indicating that oxidized ADM directly attack the enzyme, which loses its activity. Other mitochondrial enzymes, including NADH dehydrogenase, NADH oxidase and cytochrome c oxidase, were little sensitive to ADM with HRP-H(2)O(2). SDH was also sensitive to other anthracycline drugs except for aclarubicin. Mitochondrial creatine kinase (CK), which is attached to the outer face of the inner membrane of muscle mitochondria, was more sensitive to anthracyclines than SDH. SDH and CK were inactivated with loss of red color of anthracycline, indicating that oxidative activation of the B ring of anthracycline has a crucial role in inactivation of enzymes. Presumably, oxidative semiquinone or quinone produced from anthracyclines participates in the enzyme inactivation.
Muraoka
Sanae
S
Department of Biochemistry, Hokkaido College of Pharmacy, Katsuraoka-cho 7-1, Otaru 047-0264, Japan.
Miura
Toshiaki
T
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology*; D004579:Electron Transport; D006735:Horseradish Peroxidase / Q000494:pharmacology*; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D008929:Mitochondria, Heart / Q000201:enzymology*; D017382:Reactive Oxygen Species; D013385:Succinate Dehydrogenase / Q000037:antagonists & inhibitors*; D013552:Swine
D000903:Antibiotics, Antineoplastic; D017382:Reactive Oxygen Species; D004317:Doxorubicin; D006861:Hydrogen Peroxide; D006735:Horseradish Peroxidase; D013385:Succinate Dehydrogenase