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Abstract
We recently reported a cardioselective and cumulative oxidation of cardiac mitochondrial
DNA (mtDNA) following subchronic administration of doxorubicin to rats. The mtDNA
adducts persist for up to 5 weeks after cessation of doxorubicin treatment. Since
the evidence suggests that this persistence of mtDNA adducts cannot be attributed
to a lack of repair and replication, we investigated whether it might reflect a long-lasting
stimulation of free radical-mediated adduct formation. Male Sprague-Dawley rats received
weekly s.c. injections of either doxorubicin (2 mg/kg) or an equivalent volume of
saline. Cardiac myocytes isolated from rats following 6 weekly injections of doxorubicin
expressed a much higher rate of reactive oxygen species (ROS) formation compared to
saline controls. This higher rate of ROS formation persisted for 5 weeks following
the last injection. Associated with this was a persistent depression of GSH in heart
tissue, while protein-thiol content was not markedly altered. These data suggest that
the accumulation and persistence of oxidized mtDNA may be due, not to the stability
of the adducts, but to some as yet undefined toxic lesion that causes long-lasting
stimulation of ROS generation by doxorubicin. This persistent generation of ROS may
contribute to the cumulative and irreversible cardiotoxicity observed clinically with
the drug.