Abstract Body: Background: Anthracyclines such as doxorubicin (Dox) are highly effective anti-tumor agents, but their use is limited by dose-dependent cardiomyopathy. Our laboratory previously reported that activation of cytochrome P450 family 1 (Cyp1) enzymes contributes to acute doxorubicin (Dox) cardiotoxicity in zebrafish and in mice, and that potent Cyp1 inhibitors prevent cardiotoxicity. However, the role of Cyp1 enzymes in chronic Dox cardiomyopathy, as well as the mechanisms underlying cardioprotection associated with Cyp1 inhibition, have not been fully elucidated.

Objective: This study aims to define the role of Cyp1 inhibition in mouse models that more accurately recapitulates the chronic cardiomyopathy seen in patients.

Methods: The function of Cyp1 enzymes was evaluated using a small molecule Cyp1 inhibitor in wild-type (WT) mice, or Cyp1-null mice (Cyp1a1/1a2^-/-, Cyp1b1^-/-, and Cyp1a1/1a2/1b1^-/-). Low-dose Dox was administered by serial intraperitoneal or intravenous injections, respectively. Expression of Cyp1 isoforms was measured by RT-qPCR, and myocardial tissue was isolated from the left ventricle for RNA sequencing. Cardiac function was evaluated by transthoracic echocardiography.

Results: In WT mice, Dox treatment was associated with a decrease in Cyp1a2 and an increase in Cyp1b1expression in the heart and in the liver. Co-treatment of WT mice with Dox and the potent Cyp1 inhibitor YW-130 protected against cardiac dysfunction compared to Dox treatment alone. Cyp1a1/1a2^-/- and Cyp1a1/1a2/1b1^-/- mice were protected from Dox cardiomyopathy compared to WT mice. Male, but not female, Cyp1b1^-/- mice had increased cardiac dysfunction following Dox treatment compared to WT mice. RNA sequencing of myocardial tissue showed upregulation of Fundc1 and downregulation of Ccl21c in Cyp1a1/1a2^-/- mice treated with Dox, implicating changes in mitophagy and chemokine-mediated inflammation as possible mechanisms of Cyp1a-mediated cardioprotection.

Conclusions: Taken together, this study highlights the potential therapeutic value of Cyp1a inhibition in mitigating anthracycline cardiomyopathy.