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Fluconazole-induced hepatic cytochrome P450 gene expression and enzymatic activities in rats and mice

Guobin Sun1, Sheau-Fung Thai, Guy R Lambert

  • 1National Health and Environmental Effects Research Laboratory, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, NC 27711, USA.

Toxicology Letters
|January 13, 2006
PubMed

Insights

The antifungal fluconazole significantly induced cytochrome P450 (CYP) enzymes and gene expression in rat and mouse livers. This study highlights fluconazole

Area of Science:

  • Pharmacology
  • Toxicology
  • Biochemistry

Background:

  • Cytochrome P450 (CYP) enzymes are crucial for drug metabolism and detoxification.
  • Triazole antifungal agents, like fluconazole, can interact with CYP enzymes.
  • Understanding these interactions is vital for predicting drug efficacy and potential toxicity.

Purpose of the Study:

  • To investigate the impact of fluconazole on hepatic CYP gene expression and enzyme activities.
  • To compare these effects in male Sprague-Dawley rats and male CD-1 mice.
  • To determine dose-dependent responses to fluconazole administration.

Main Methods:

  • Administration of fluconazole (2, 25, or 50 mg/kg bw/d) to rats and mice for 14 days.
  • Measurement of hepatic microsomal enzyme activities using alkoxyresorufin O-dealkylation (AROD) assays.
  • Quantification of CYP mRNA expression via quantitative real-time reverse-transcription polymerase chain reaction (qRT-PCR).
  • Identification of specific CYP isoforms using Western blot analyses.

Main Results:

  • In rats, fluconazole significantly induced CYP2B1 and CYP3A23/3A1 mRNA expression and protein levels, with marked increases in PROD, BROD, and EROD activities.
  • In mice, fluconazole induced Cyp2b10 and Cyp3a11 mRNA expression and hepatic microsomal activities (BROD, PROD, EROD, MROD) at higher doses.
  • Fluconazole demonstrated a clear induction of CYP2B and CYP3A families in both rat and mouse livers.

Conclusions:

  • Fluconazole is a potent inducer of hepatic CYP2B and CYP3A families in rats and mice.
  • These findings underscore the potential for drug-drug interactions involving fluconazole and other substances metabolized by these CYP isoforms.
  • Further research is warranted to elucidate the clinical implications of fluconazole-induced CYP modulation.

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