Citation:

SUN, G., R. GRINDSTAFF, S. Y. THAI, G. LAMBERT, D. B. TULLY, D. J. DIX, AND S. NESNOW. INDUCTION OF CYTOCHROME P450 ISOFORMS IN RAT LIVER BY TWO CONAZOLES, TRIADIMEFON AND MYCLOBUTANIL. XENOBIOTICA. Taylor & Francis, Inc., Philadelphia, PA, 37(2):180-193, (2007).

Impact/Purpose:

to examine the inductive effects of two triazole antifungal agents, myclobutanil and triadimefon on the expression of hepatic cytochrome P450 (CYP) genes and on the activities of CYP enzymes

Description:

1. This study was undertaken to examine the inductive effects of two triazole antifungal agents, myclobutanil and triadimefon on the expression of hepatic cytochrome P450 (CYP) genes and on the activities of CYP enzymes in male Sprague-Dawley rats. Rats were dosed by gavage for 14 days with myclobutanil and triadimefon at several dose levels including their maximum tolerated doses (MTD).


2. Both myclobutanil and triadimefon induced pentoxyresorufin O-dealkylase activities at their MTD levels: myclobutanil, 8.1-fold at 150 mg/kg-bw/d. and triadimefon, 18.5-fold at 115 mg/kg-bw/d. Benzyloxyresorufin O-dealkylase activities were similarly increased: myclobutanil, 13.3-fold, triadimefon, 27.7-fold.


3. Quantitative real-time reverse-transcription polymerase chain reaction assays were used to characterize the mRNA expression of specific CYP genes induced by these two conazoles. Myclobutanil and triadimefon treatment at their MTD levels significantly increased rat hepatic mRNA expression of CYP2B1 (14.3-, 54.6-fold), CYP3A23/3A1 (2.2, 7.3-fold), and CYP3A2 (1.5-, 1.7-fold).


4. Western immunoblots of rat hepatic microsomal proteins identified significantly increased levels of CYP isoforms by myclobutanil and triadimefon: CYP2B1/2 (4.8-, 5.3-fold), CYP3A1 (2.2-, 2.9-fold). Triadimefon also increased CYP3A2 immunoreactive protein levels 1.8-fold. These results indicate that triadimefon and myclobutanil, like other triazole-containing conazoles, induced CYP2B and CYP3A families of cytochromes in rat liver.

Record Details: