Protection from Doxorubicin-induced Cardiac Toxicity in Mice with a Null Allele of Carbonyl Reductase 1

Doxorubicin is a highly effective antineoplastic agent, but it can produce the serious side effects of acute cardiac injury and chronic congestive heart failure. Carbonyl reductase (CBR) has been implicated in the development of doxorubicin-induced cardiotoxicity. To test whether a decrease in CBR levels was protective against doxorubicin toxicity, we created a null allele of the Cbr1 gene. Mice with one functional copy of the gene (Cbr1 +/-) were healthy and grossly normal despite having decreased levels of Cbr1 transcript and protein. Control and Cbr1 +/- mice were administered doxorubicin at 20 mg/kg i.p. Cbr1 +/- mice showed decreased circulating levels of the cardiotoxic metabolite, doxorubicinol, after administration. Within 2 weeks, 91% of wild-type mice were severely affected (n = 11) compared with 18% of Cbr1 +/- mice (n = 11). Echocardiography and histological analysis showed that Cbr1 +/- mice were protected from gross and cellular level pathologies associated with doxorubicin treatment. Demonstration that inhibition of carbonyl reductase blocks the toxic effects on the heart has important implications for improving the use of doxorubicin in chemotherapy.