Induction of the NAD(P)H:quinone oxidoreductase 1 by ketoconazole and itraconazole: A mechanism of cancer chemoprotection

Abstract

Studies in many carcinogen-induced animal models and cell lines demonstrated that azole antifungal drugs are therapeutically effective against different types of cancer. Yet, the molecular mechanisms involved are still poorly understood. Therefore, we examined the ability of three structurally different antifungal drugs, ketoconazole (KTZ), itraconazole (ITZ), and fluconazole (FLZ) to induce the expression of NAD(P)H:quinone oxidoreductase 1 (Nqo1), an enzyme known to play an important role in xenobiotic and carcinogen detoxifications. We showed that KTZ and ITZ, but not FLZ, induced Nqo1 mRNA and enzymatic activity levels in a concentration- and time-dependent manner in wild-type but not aryl hydrocarbon receptor (AhR)-deficient Hepa 1c1c7 cells. Furthermore, KTZ and ITZ increased Nqo1 de novo RNA synthesis without significantly affecting the levels of existing RNA, suggesting a transcriptional mechanism is involved. This study provides the first evidence for the ability of KTZ and ITZ to induce the Nqo1 gene expression through an AhR-dependent mechanism.