Bicarbonate exacerbates oxidative injury induced by antitumor antibiotic doxorubicin in cardiomyocytes

Doxorubicin, a broad-spectrum antitumor antibiotic, causes dose-dependent c ardiomyopathy and heart failure. Although the exact molecular mechanisms of cardiotoxicity are not well established, oxidative mechanisms involving do xorubicin-induced superoxide anion production have been proposed. In this s tudy, we show that bicarbonate, a physiologically relevant tissue component , greatly amplified doxorubicin-induced cardiomyocyte injury. Bicarbonate a lso enhanced inactivation of aconitase, a crucial tricarboxylic acid cycle enzyme, in cardiomyocytes exposed to doxorubicin. The cell-permeable supero xide dismutase mimetic, Mn( III) tetrakis (4-benzoic acid) porphyrin, rever sed doxorubicin-induced cardiomyocyte injury. Bicarbonate enhanced the inac tivation of purified mitochondrial aconitase in the xanthine/xanthine oxida se system, generating superoxide. The results suggest that bicarbonate ampl ifies the prooxidant effect of superoxide. Bicarbonate also caused an incre ased loading of cardiomyocytes with doxorubicin. We conclude that the bicar bonate-mediated increase in doxorubicin toxicity is due to increased intrac ellular loading of doxorubicin in cardiomyocytes and subsequent exacerbatio n of superoxide-mediated cardiomyocyte injury.