Conazoles comprise a class of fungicides used in agriculture and as
pharmaceutical products. The fungicidal properties of conazoles are due to their inhibition of
ergosterol biosynthesis. Certain conazoles are tumorigenic in rodents; both
propiconazole and
triadimefon are hepatotoxic and hepatotumorigenic in mice, while
myclobutanil is not a mouse liver tumorigen. As a component of a large-scale study aimed at determining the mode(s) of action for tumorigenic conazoles, we report the results from comparative evaluations of liver and
body weights, liver histopathology, cell proliferation,
cytochrome P450 (CYP) activity, and serum
cholesterol,
high-density lipoprotein and
triglyceride levels after exposure to
propiconazole,
triadimefon, and
myclobutanil. Male CD-1 mice were treated in the feed for 4, 30, or 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 metabolizing
enzyme activity.
PROD activities exceeded those of
MROD, and
EROD with
propiconazole inducing the highest activities of
PROD. Mice had similar patterns of dose-dependent increases in hepatocyte
hypertrophy after exposure to the 3 conazoles. High-dose exposures to
propiconazole and
myclobutanil, but not
triadimefon, were associated with early (4 days) increases in cell proliferation. All the chemicals at high doses reduced serum
cholesterol and
high-density lipoprotein (HDL) levels at 30 days of treatment, while only
triadimefon had this effect at 4 days of treatment and only
myclobutanil and
propiconazole at 90 days of treatment. Overall, the tumorigenic and nontumorigenic conazoles induced similar effects on mouse liver CYP
enzyme activities and pathology. There was no specific pattern of tissue responses that could consistently be used to differentiate the tumorigenic conazoles,
propiconazole, and
triadimefon, from the nontumorigenic
myclobutanil. These findings serve to anchor other transcriptional profiling studies aimed at probing differences in key events and modes of action for tumorigenic and nontumorigenic conazoles.