Initiation and promotion of altered hepatic foci in female rats and inhibition of cell-cell communication by the imidazole fungicide prochloraz

The imidazole fungicide prochloraz (1-[N-propyl-N-2-(2,4,6-trichlorophenoxy) ethyl carbamoyl] imidazole) was investigated for its ability to inhibit gap junctional intercellular communication in the scrape-loading/dye-transfer assay in IAR 20 rat liver epithelial cells and for effects on the initiation and promotion stages of hepatocarcinogenesis. Female Sprague-Dawley rats initiated with N-nitrosodiethylamine 24-hr after partial hepatectomy were administered prochloraz five days a week by oral gavage (30 or 150 mg/kg) for 10 weeks. Altered hepatic foci (AHF) were analyzed by quantitative stereology from liver sections stained for γ-glutamyltranspeptidase (GGT) and glutathione S-transferase P (GST-P). The fungicide was also studied for its ability to initiate the development of GGT-positive AHF in rat liver. The in vitro studies showed prochloraz to be an inhibitor of cell-cell communication in the test system used. In the in vivo studies, prochloraz showed no effect on the initiation of GGT-positive foci. However, significant increases in the percentage of liver tissue occupied by GGT-positive AHF and the number of GST-P-positive AHF per cm3 in initiated animals were recorded in the low dose group. The present data suggest that prochloraz acts as a weak tumour promoter of hepatocarcinogenesis but does not initiate this process.