Propiconazole is a
triazole-containing fungicide that is used agriculturally on grasses, fruits, grains, seeds, hardwoods, and conifers.
Propiconazole is a mouse liver hepatotoxicant and a hepatocarcinogen that has adverse reproductive and developmental toxicities in experimental animals. The goal of this study was to investigate the cytotoxic responses of
propiconazole and its metabolites to determine if metabolism of this agent differentially affected its cytotoxic activities in hepatic tumor cell lines and in primary hepatocytes. To this end the cytotoxic effects of
propiconazole and five of its metabolites were examined in three hepatic cell types: The mouse
hepatoma Hepa1c1c7 cell line, the human
hepatoma HepG2 cell line, and primary cultures of mouse hepatocytes. We initially compared the responses of
propiconazole exposure in both Hepa1c1c7 and HepG2 cell lines over a concentration range of 0-200 microM using two assay systems: The
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and the
neutral red assay. Concentration-related cytotoxic responses were evident in both cell lines using both endpoints with the MTT assay providing enhanced sensitivity. The relative cytotoxic effects of
propiconazole and five
propiconazole metabolites were further assessed by the MTT assay using Hepa1c1c7 and HepG2 tumor cell lines. The cell cultures were exposed to various concentrations of
propiconazole and five of its metabolites over a range of 0-400 microM.
Propiconazole was cytotoxic in both cell lines in a dose-dependent manner. All five metabolites were less cytotoxic in both cell lines compared to the parent compound. The most cytotoxic metabolites in Hepa1c1c7 and HepG2 cells among the five were 3-(2-((1H-1,2,4-triazol-1-yl)methyl)-2-(2,4-dichlorophenyl)-1,3-dioxolan-4-yl)propan-1-ol and 1-(2-((1H-1,2,4-triazol-1-yl)methyl)-2-(2,4-dichlorophenyl)-1,3-dioxolan-4-yl)propan-2-ol.
Propiconazole was cytotoxic in primary mouse hepatocytes; however none of the five
propiconazole metabolites exerted cytotoxic activities. There was a linear relationship between the cLogP and the cytotoxic effects of
propiconazole and its five metabolites in Hepa1c1c7 cells. We conclude that these
propiconazole metabolites would not contribute to the
propiconazole-induced cytotoxicity process in primary mouse hepatocytes. Furthermore, since in tumor cell lines the metabolites were less cytotoxic than the parent
propiconazole, our results suggest that in the
tumorigenesis process as
tumor cells are formed they would be more susceptible to the cytotoxic effects of
propiconazole compared to the metabolites.