Effect of doxorubicin-enhanced hydrogen peroxide and hydroxyl radical formation on calcium sequestration by cardiac sarcoplasmic reticulum.
This study investigated the effect of doxorubicin-related oxygen radical formation on Ca2+ uptake by rat heart sarcoplasmic reticulum vesicles. Enzymatic activation of doxorubicin by cardiac NADH dehydrogenase produced a dose-related inhibition of Ca2+ uptake that was enzyme- and cofactor-dependent and that was inhibited by catalase, various hydroxyl radical scavengers, and the iron chelator deferoxamine. Furthermore, inhibition of Ca2+ uptake paralleled the production of the hydroxyl radical by NADH dehydrogenase after doxorubicin treatment. These results suggest that doxorubicin-stimulated reactive oxygen metabolism can alter Ca2+ transport by cardiac sarcoplasmic reticulum and may represent one pathway involved in the cardiac toxicity of this potent antineoplastic agent.
Harris
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Doroshow
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JH
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002374:Catalase / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology*; D006861:Hydrogen Peroxide / Q000096:biosynthesis*; D006878:Hydroxides; D017665:Hydroxyl Radical; D009206:Myocardium / Q000378:metabolism* / Q000648:ultrastructure; D009245:NADH Dehydrogenase / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*
D006878:Hydroxides; D017665:Hydroxyl Radical; D004317:Doxorubicin; D006861:Hydrogen Peroxide; D002374:Catalase; D009245:NADH Dehydrogenase; D002118:Calcium