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COMPARATIVE LIVER P450 ENZYME ACTIVITY AND HISTOPATHOLOGY IN MICE TREATED WITH THE CONAZOLE FUNGICIDES: MYCLOBUTANIL, PROPICONAZOLE AND TRIADIMETON
Citation:
Allen, J W., G M. Nelson, E. Winkfield, S D. Hester, M H. George, G. Sun, S. C. Nesnow, D C. Wolf, S. F. Thai, D. A. Delker, B C. Roop, S. A. Leavitt, AND W. O. Ward. COMPARATIVE LIVER P450 ENZYME ACTIVITY AND HISTOPATHOLOGY IN MICE TREATED WITH THE CONAZOLE FUNGICIDES: MYCLOBUTANIL, PROPICONAZOLE AND TRIADIMETON. Presented at Society of Toxicology, New Orleans, LA, March 6-10, 2005.
Description:
Conazoles used in agriculture and pharmaceutical products comprise a class of chemicals which inhibit ergosterol biosynthesis to act as fungicides. Both propiconazole and triadimefon are hepatotoxic and hepatotumorigenic in mice, while myclobutanil is not a mouse liver tumorigen. The tumorigenic activities of these conazoles are thought to be mediated through increased liver cytochrome P450 enzyme activity leading to oxidative stress, mitogenesis and altered foci development. We have assessed how P450 enzyme activity and liver pathology correlate with known hepatotumorigenic response to conazoles. Male CD-1 mice were treated in the feed for 4, 30 and 90 days with triadimefon (0, 100, 500 or 1800 ppm), propiconazole (0, 100, 500 or 2500 ppm) or myclobutanil (0, 100, 500 or 2000 ppm). Alkoxyresorufin O-dealkylation (AROD) assays indicated that all 3 chemicals induced similar patterns of dose-related increases in pentoxyresorufin O-dealkylation (PROD), and to a lesser extent, ethoxyresorufin O-dealkylation and/or methoxyresorufin O-dealkylation. Propiconazole high-dose exposures over 30 and 90 days induced 36-38 fold higher levels of PROD, concomitant with 2-fold higher liver weights (as % body weights), as compared with controls. Liver histopathology revealed similar dose-dependent hypertrophy following exposure to all 3 conazoles. There were no significant treatment effects on body weight. Overall, with the exception of some highest-level effects observed for propiconazole, a similar induction pattern for these specific AROD-assayed liver enzymes and histopathologies was observed for the 3 conazoles, regardless of their tumorigenicity.