Cyp1 Inhibition Prevents Doxorubicin‐Induced Cardiomyopathy in a Zebrafish Heart‐Failure Model

Doxorubicin is a highly effective chemotherapy agent used to treat many common malignancies. However, its use is limited by cardiotoxicity, and cumulative doses exponentially increase the risk of heart failure. To identify novel heart failure treatment targets, we previously established a zebrafish model of doxorubicin-induced cardiomyopathy for small molecule screening. Using this model, we previously identified several small molecules that prevent doxorubicin-induced cardiotoxicity both in zebrafish as well as in mouse models. In this study, we have expanded our exploration of doxorubicin cardiotoxicity by screening 2,271 small molecules from a proprietary, target-annotated tool compound collection. We found 120 small molecules that can prevent doxorubicin-induced cardiotoxicity, including seven highly-effective compounds. Of these, all seven exhibited inhibitory activity towards Cytochrome P450 family 1 (CYP1). These results are consistent with our previous findings in which visnagin, a CYP1 inhibitor, also prevented doxorubicin-induced cardiotoxicity. Importantly, genetic mutation of cyp1a protected zebrafish against doxorubicin-induced cardiotoxicity phenotypes. Together, these results provide strong evidence that CYP1 is an important contributor to doxorubicin-induced cardiotoxicity and highlight the CYP1 pathway as a candidate therapeutic target for clinical cardioprotection.