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.