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Fluconazole Inhibits Cytochrome P450 1B1 and its Associated Arachidonic Acid Metabolites in the Heart and Protects against Angiotensin II‐induced Cardiac Hypertrophy

Cytochrome P450 1B1 (CYP1B1) has been reported to have a major role in metabolizing arachidonic acid (AA) into cardiotoxic metabolites, mid‐chain hydroxyeicosatetraenoic acid (HETEs). Of particular interest, several studies have demonstrated the role of mid‐chain HETEs in the development of cardiac hypertrophy. Recently, we have shown that fluconazole inhibits the formation of mid‐chain HETEs metabolite, however, whether fluconazole would be able to modulate CYP1B1‐mediated AA metabolism in an Ang II‐induced cellular hypertrophy model and in rats' heart has never been investigated before. Therefore, the objectives of this study were; 1) to investigate the effect of fluconazole on CYP1B1 mediated AA metabolites and to explore the potential protective effect against Ang II‐induced cellular hypertrophy, and 2) to study the effect of fluconazole on CYP1B1 and its associated AA metabolites in vivo in Sprague Dawley rats. For this purpose, both H9c2 and RL‐14 cells were treated with 10 μM Ang II in the absence and presence of 50 μM fluconazole for 24 hours. Also, Sprague Dawley rats (n=6) were injected intraperitoneally with a single dose of fluconazole (20 mg/kg) or saline and the heart tissues were harvested 24 hours post‐treatment. Thereafter, the formation of AA metabolites was measured using liquid chromatography‐electron spray ionization‐mass spectrometry (LC‐ESI‐MS). Whereas, the expression of cardiac hypertrophic markers and CYP1B1 were determined by real time‐polymerase chain reaction and Western blot analysis, respectively. Moreover, enzymatic activity and determination of CYP1B1 inhibition kinetics by fluconazole were assessed using 7‐ethoxyresorufin O‐deethylase (EROD) and recombinant human CYP1B1 assays. Our results demonstrated that fluconazole was able to attenuate Ang‐II‐induced cellular hypertrophy as evidenced by a significant inhibition of hypertrophic markers, β‐myosin heavy chain (MHC)/ α‐MHC, BNP as well as cell surface area. The protective effect of fluconazole was associated with a significant decrease in the level of CYP1B1 gene, protein, activity levels and its associated mid‐chain HETEs metabolite induced by Ang II. Furthermore, treatment of rats with fluconazole significantly decreased the expression of CYP1B1 enzyme and the formation level of cardiotoxic mid‐chain HETEs metabolites in the heart. In conclusion, our results showed that fluconazole protects against Ang II‐induced cellular hypertrophy by inhibiting CYP1B1 and its associated mid‐chain HETEs metabolites. Also, fluconazole may be repurposed as a mid‐chain HETEs formation inhibitor for the treatment of cardiac hypertrophy and heart failure.