title: Bicarbonate exacerbates oxidative injury induced by antitumor antibiotic doxorubicin in cardiomyocytes.
abstract: Doxorubicin, a broad-spectrum antitumor antibiotic, causes dose-dependent cardiomyopathy and heart failure. Although the exact molecular mechanisms of cardiotoxicity are not well established, oxidative mechanisms involving doxorubicin-induced superoxide anion production have been proposed. In this study, we show that bicarbonate, a physiologically relevant tissue component, greatly amplified doxorubicin-induced cardiomyocyte injury. Bicarbonate also enhanced inactivation of aconitase, a crucial tricarboxylic acid cycle enzyme, in cardiomyocytes exposed to doxorubicin. The cell-permeable superoxide dismutase mimetic, Mn(III)tetrakis (4-benzoic acid) porphyrin, reversed doxorubicin-induced cardiomyocyte injury. Bicarbonate enhanced the inactivation of purified mitochondrial aconitase in the xanthine/xanthine oxidase system, generating superoxide. The results suggest that bicarbonate amplifies the prooxidant effect of superoxide. Bicarbonate also caused an increased loading of cardiomyocytes with doxorubicin. We conclude that the bicarbonate-mediated increase in doxorubicin toxicity is due to increased intracellular loading of doxorubicin in cardiomyocytes and subsequent exacerbation of superoxide-mediated cardiomyocyte injury.
authors.affiliation: Biophysics Research Institute and Free Radical Reseach Center, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
authors.forename: E A
authors.initials: EA
authors.lastname: Konorev
authors.forename: H
authors.initials: H
authors.lastname: Zhang
authors.forename: J
authors.initials: J
authors.lastname: Joseph
authors.forename: M C
authors.initials: MC
authors.lastname: Kennedy
authors.forename: B
authors.initials: B
authors.lastname: Kalyanaraman
mesh_terms: D000154:Aconitate Hydratase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D017920:Antiporters / Q000037:antagonists & inhibitors; D001639:Bicarbonates / Q000378:metabolism* / Q000494:pharmacology; D002478:Cells, Cultured; D027963:Chloride-Bicarbonate Antiporters; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000633:toxicity*; D004357:Drug Synergism; D004578:Electron Spin Resonance Spectroscopy; D005110:Extracellular Space / Q000378:metabolism; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D007424:Intracellular Fluid / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D016877:Oxidants / Q000096:biosynthesis; D010084:Oxidation-Reduction / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D019097:Spin Trapping; D013481:Superoxides / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D017920:Antiporters; D001639:Bicarbonates; D027963:Chloride-Bicarbonate Antiporters; D016877:Oxidants; D013481:Superoxides; D004317:Doxorubicin; D000154:Aconitate Hydratase