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MYCLOBUTANIL AND TRIADIMEFON METHABOLISM BY RAT CYP ISOFORMS AND LIVER MICROSOMES
Citation:
Tang, J., Y M. Sey, R. Murrel, J C. Rockett, D J. Dix, AND H A. Barton. MYCLOBUTANIL AND TRIADIMEFON METHABOLISM BY RAT CYP ISOFORMS AND LIVER MICROSOMES. Presented at Society of Toxicology Annual Meeting, New Orleans, LA, March 06 - 10, 2005.
Description:
The mode of action of conazole fungicides is to inhibit cytochrome P450 (CYP) 51 activity and thus the biosynthesis of ergosterol by fungi. Conazoles can also modulate other CYP activities in vertebrate species including humans. Myclobutanil (MCL) and triadimefon (TRD) are agricultural conazoles with similar chemical structures. Laboratory animal studies have shown MCL and TRD have reproductive toxicity and carcinogenic activity, respectively. It has been proposed that modulation of CYP activity may be the common mechanism underlying their toxic effects. This study was designed to investigate 1) whether MCL and TRD modulated rat CYP activities that results in changes to conazole metabolism, and 2) which rat CYP isoforms were responsible for conazole metabolism. Liver microsomes were prepared from adult male Sprague-Dawley rats exposed orally to vehicle, MCL (10 or 150 mg/kg), or TRD (5 or 115 mg/kg) for 14 days. Total P450 concentrations in both high dosage groups were significantly higher (P<0.01) than vehicle control. The rate of MCL disappearance when incubated with microsomes was much more rapid than for TRD, and the disappearance rate for both chemicals increased with microsomes from rats exposed to higher dose of either chemical vesus control. Incubation of MCL with recombinant rat CYP isoforms indicated that CYP2C6, 2C11, 3A1, and 3A2 had metabolized myclobutanil, but not CYP2B1, 1A1, 1A2, 2A1, 2A2, 2C12, 2C13, 2D1, 2D2, and 2E1. CYP2C6 and 3A1 were the only isoforms responsible for TRD metabolism but at a much lower rate. These results indicate that both MCL and TRD induce CYP activities that led to modest increases in their own metabolism. (This abstract does not reflect EPA policy. JT is supported by EPA/UNC Toxicology Training Agreement # CT827206. RM is supported by EPA/NCSU Training Agreement # CT826512010)