The effect of fluconazole on cytochrome P450 1B1, formation of arachidonic acid metabolites, and protection against angiotensin II-induced cardiac hypertrophy

Abstract

Several studies have elucidated the role of cytochrome P450s (CYPs) and their associated arachidonic acid (AA) metabolites in development of cardiac hypertrophy. CYP1B1 has been reported to have a major role in metabolizing 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, fluconazole was shown to inhibit 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. 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. Our study provides the first evidence that fluconazole may be repurposed as a mid-chain HETEs formation inhibitor for the treatment of cardiac hypertrophy and heart failure.