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PROPICONAZOLE-INDUCED CYTOCHROME P450 GENE EXPRESSION AND ENZYMATIC ACTIVITIES IN RAT AND MOUSE LIVER
Citation:
SUN, G., S. Y. THAI, D. B. TULLY, G. R. LAMBERT, A. K. GOETZ, D. C. WOLF, D. J. DIX, AND S. NESNOW. PROPICONAZOLE-INDUCED CYTOCHROME P450 GENE EXPRESSION AND ENZYMATIC ACTIVITIES IN RAT AND MOUSE LIVER. TOXICOLOGY LETTERS. Elsevier Ireland Limited, Limerick, Ireland, 155(2):277-287, (2004).
Impact/Purpose:
to examine modulation of hepatic Cytochrome P450s in Sprague-Dawley Rats and CD-1 Mice by Four Triazole Conazoles
Description:
Conazoles are N-substituted azole antifungal agents used as both pesticides and drugs. Some of these compounds are hepatocarcinogenic in mice and some can induce thyroid tumors in rats. Many of these compounds are able to induce and/or inhibit mammalian hepatic cytochrome P450s that are responsible for the metabolism of endogenous as well as exogenous compounds including drugs and xenobiotic chemicals. In the present study, four triazole containing conazoles fluconazole, myclobutanil, propiconazole, and triadimefon were studied for their effects on hepatic cytochrome P450s in Sprague-Dawley rats and CD-1 mice. Alkoxyresorufin O-dealkylation (AROD) methods were used as measures of P450 enzyme activities. Animals were administered the following compounds by gavage daily for 14 days: fluconazole (2, 25, and 50 mg/kg body weight), myclobutanil (10, 75, and 150 mg/kg body weight), propiconazole (10, 75, and 150 mg/kg body weight), or triadimefon (5, 50, and 115 mg/kg body weight). Animals were sacrificed 24 hrs after the last dosing and hepatic microsomes were prepared. Each conazole significantly induced pentoxyresorufin O-dealkylation and benzyloxyresorufin O-dealkylation at mid and high doses in liver microsomes of both rats and mice. No induction or slight induction of methoxyresorufin O-dealkylation or ethoxyresorufin O-dealkylation was detected. Triadimefon was the most potent AROD inducer in rats. Fluconazole was the most potent AROD inducer in mice. The selectivities of AROD were also studied using recombinant rat liver P450s. Our results indicate that these four triazole based conazoles induced cytochrome 2B and/or 3A families of isozymes.
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