Induction of cytochrome P450 1A1 by ketoconazole and itraconazole but not fluconazole in murine and human hepatoma cell lines.

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Korashy HM, Shayeganpour A, Brocks DR, El-Kadi AO

Induction of cytochrome P450 1A1 by ketoconazole and itraconazole but not fluconazole in murine and human hepatoma cell lines.

Toxicol Sci. 2007 May;97(1):32-43. Epub 2007 Feb 5.

PubMed ID

17283379 [ View in PubMed

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Abstract

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.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Itraconazole	Cytochrome P450 1A1	Protein	Humans	No	Inducer	Details
Ketoconazole	Cytochrome P450 1A1	Protein	Humans	Unknown	Inhibitor Inducer	Details

Pharmaco-transcriptomics

Drug	Drug Groups	Gene	Gene ID	Change	Interaction	Chromosome
Itraconazole	Approved Investigational	CYP1A1	1543	upregulated	Itraconazole results in increased expression of CYP1A1 mRNA	15q24.1
Ketoconazole	Approved Investigational	CYP1A1	1543	upregulated	Ketoconazole results in increased expression of CYP1A1 mRNA	15q24.1