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IN VITRO METABOLISM OF TRIADIMEFON BY RAT LIVER MICROSOMES
Citation:
SEY, Y. M., H. A. BARTON, AND D. J. DIX. IN VITRO METABOLISM OF TRIADIMEFON BY RAT LIVER MICROSOMES. Presented at 45th Annual Society of Toxicology Meeting 2006, San Diego, CA, March 05 - 09, 2006.
Description:
Triadimefon (TDF) is an azole used as an agricultural pesticide. TDF exposures in laboratory studies have resulted in neurological, developmental and reproductive toxicities as well as tumors. Other classes of conazoles serve as effective pharmaceutical agents in controlling local and systemic fungal infections in humans. The antifungal mode of action is inhibition of cytochrome P450 (CYP) 51 activity and ergosterol biosynthesis. Conazoles have been shown to modulate hepatic xenobiotic metabolizing enzymes which can influence toxicity. CYP mediated TDF metabolism results in minor hydroxylated metabolites, however, the reduction to the major metabolite triadimenol is mediated by an unidentified carbonyl reductase. This study aimed to investigate whether triadimefon modulates rat xenobiotic metabolizing enzymes and whether such effects alter triadimefon metabolism. Liver microsomes were prepared from adult male Sprague Dawley rats gavaged with control, 5 or 115 mg/kg TDF for 14 days. Total P450 concentration in the high dosage group was significantly higher than in both control and low dose groups indicating enzyme induction at this dose. Enzyme induction in the high dosage group resulted in significantly increased TDF microsomal metabolic clearance (intrinsic) relative to non-induced groups. For control and low dose animals, Km (~ 1 ?M) was determined to be similar while high dose animals showed a slightly lower value. However, no statistically significant differences in Km were apparent across all dose groups. These data indicated that repeated TDF exposure can induce enzyme activity which resulted in increased TDF metabolism. (This abstract does not necessarily reflect EPA Policy).