ToxSci Advance Access originally published online on February 5, 2007
Toxicological Sciences 2007 97(1):32-43; doi:10.1093/toxsci/kfm012
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Induction of Cytochrome P450 1A1 by Ketoconazole and Itraconazole but not Fluconazole in Murine and Human Hepatoma Cell Lines
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada T6G 2N8
1 To whom correspondence should be addressed at Faculty of Pharmacy and Pharmaceutical Sciences, 3126 Dentistry/Pharmacy Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2N8. Fax: +1 780 492 1217. E-mail: aelkadi{at}pharmacy.ualberta.ca.
Received December 8, 2006; accepted January 26, 2007
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Abstract |
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Azole antifungal agents are widely prescribed drugs for the treatment of systemic fungal infections; however, since their introduction into the market, increasing evidences of hepatotoxicity have been reported. Therefore, we examined here the ability of three structurally different antifungal drugs, ketoconazole (KTZ), itraconazole (ITZ), and fluconazole (FLZ) to induce the CYP1A1, an enzyme known to play an important role in chemical activation of xenobiotics to toxic metabolites. KTZ and ITZ, but not FLZ, induced the CYP1A1 in murine Hepa 1c1c7 and human HepG2 hepatoma cells at the mRNA, protein and activity levels in a concentration- and time-dependent manner. The increases in Cyp1a1 mRNA levels mediated by KTZ and ITZ were completely blocked by the RNA synthesis inhibitor, actinomycin D, whereas the level of existing mRNA was not altered, implying a requirement of de novo RNA synthesis through a transcriptional mechanism. The ability of these drugs to directly activate the aryl hydrocarbon receptor (AhR) transformation and hence xenobiotic responsive element's binding was strongly correlated with their abilities to induce luciferase activity. Inhibition studies showed that KTZ and ITZ, in addition to being CYP1A1 inducers, are substrates and competitive inhibitors. This study provides the first evidence for the ability of KTZ and ITZ to induce the CYP1A1 gene expression through an AhR-dependent mechanism, and suggests a novel mechanism of the KTZ- and ITZ-mediated toxicities.
Key Words: CYP1A1; aryl hydrocarbon receptor; antifungal drugs; carcinogenesis; hepatotoxicity; transcription.