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FLUCONAZOLE-INDUCED HEPATIC CYTOCHROME P450 GENE EXPRESSION AND ENZYMATIC ACTIVITIES IN RATS AND MICE
Citation:
SUN, G., S. Y. THAI, G. LAMBERT, D. C. WOLF, D. B. TULLY, A. GOETZ, M. H. GEORGE, R. GRINDSTAFF, D. J. DIX, AND S. NESNOW. FLUCONAZOLE-INDUCED HEPATIC CYTOCHROME P450 GENE EXPRESSION AND ENZYMATIC ACTIVITIES IN RATS AND MICE . TOXICOLOGY LETTERS. Elsevier Science Ltd, New York, NY, 164(1):44-53, (2006).
Impact/Purpose:
To examine the effects of the triazole antifungal agent fluconazole on the expression of hepatic cytochrome P450 (Cyp) genes
Description:
This study was undertaken to examine the effects of the triazole antifungal agent fluconazole on the expression of hepatic cytochrome P450 (Cyp) genes and the activities of Cyp enzymes in male Sprague-Dawley rats and male CD-1 mice. Alkoxyresorufin O-dealkylation (AROD) methods were used as measures of Cyp enzyme activities. Western analyses identified specific Cyp isoforms. Quantitative real-time reverse-transcription polymerase chain reaction (quantitative real time-RT-PCR) assays were used to quantitate the mRNA expression of specific Cyp genes induced by this conazole. Rats and mice were administered fluconazole 2, 25, or 50 mg/kg-bw/d by gavage daily for 14 days. In rats, fluconazole treatment (50 mg/kg-bw/d) significantly induced pentoxyresorufin O-dealkylation (PROD), benzyloxyresorufin O-dealkylation (BROD), and ethoxyresorufin O-dealkylation (EROD) hepatic microsomal activities. Fluconazole treatment (50 mg/kg-bw/d) significantly increased rat hepatic mRNA expression of Cyp2bl (17.9-fold), Cyp3al (2.6-fold), and Cyp3a2 (1.9-fold). Western immunoblots of rat hepatic microsomal proteins identified increased amounts of the Cyp isoforms: Cyplal, Cypla2, Cyp2bl/2, Cyp3al, and Cyp3a2. In mice, fluconazole induced BROD, PROD, EROD, and methoxyresorufin O-dealkylation hepatic microsomal activities after treatment with 25 and 50 mg/kg-bw/d. Fluconazole increased mouse hepatic mRNA expression of Cypla2 (1.9-fold), Cyp2b10 (3.1-fold) and Cyp3al1 (3.9-fold) after 50 mg/kg-bw/d. In summary, these results indicated that fluconazole, a triazole-based conazole, clearly induced Cyp2b and Cyp3a families of isoforms in rat liver and Cypla, Cyp2b, and Cyp3a families of isoforms in mouse liver.