Mitochondrial regulation of superoxide by Ca2+: an alternate mechanism for the cardiotoxicity of doxorubicin.
Mitochondrial Ca2+ accumulation and the formation of reactive oxygen species are processes dependent on the electron transport system. The production of superoxide by respiring rat heart mitochondria was decreased by either chelating extramitochondrial Ca2+ with EGTA or by blocking mitochondrial Ca2+ uptake with ruthenium red. Mitochondrial experiments with doxorubicin showed an enhanced stimulation of reactive oxygen species, which was also inhibited by EGTA or ruthenium red. Myocardial cell cultures treated with doxorubicin showed an enhanced formation of intracellular reactive oxygen species, which preceded cell damage. Ruthenium red not only attenuated the enhanced formation of intracellular reactive oxygen species, but also increased cell viability. The relationship between mitochondrial Ca2+ transport and the formation of superoxide suggests that a disruption in mitochondrial Ca2+ homeostasis by doxorubicin may be involved in the release of reactive oxygen species and its cardiotoxicity.
Division of Pharmacology and Toxicology, College of Pharmacy, University of Texas, Austin 78712.
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Chacon
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Acosta
D000818:Animals; D001692:Biological Transport; D002118:Calcium / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004317:Doxorubicin / Q000633:toxicity*; D005452:Fluoresceins; D005609:Free Radicals; D006331:Heart Diseases / Q000139:chemically induced* / Q000503:physiopathology; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D008564:Membrane Potentials; D008929:Mitochondria, Heart / Q000502:physiology*; D009580:Nitroblue Tetrazolium; D051381:Rats; D011919:Rats, Inbred Strains; D012430:Ruthenium Red / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism*
D005452:Fluoresceins; D005609:Free Radicals; D013481:Superoxides; D012430:Ruthenium Red; C029569:diacetyldichlorofluorescein; D009580:Nitroblue Tetrazolium; D004317:Doxorubicin; D007770:L-Lactate Dehydrogenase; D002118:Calcium