Furan Induced Characteristic Glutathione S -Transferase Placental Form-Positive Foci in Terms of Cell Kinetics and Gene Expression.

Glutathione S -transferase placental form-positive (GST-P ⁺ ) foci are markers of preneoplastic lesions in rat hepatocarcinogenesis. Our previous studies using reporter gene transgenic rats showed that furan, a hepatocarcinogen in rodents, rapidly induces the formation of GST-P ⁺ foci after short exposure without reporter gene mutation. We hypothesized that GST-P ⁺ foci induced by furan may have biological characteristics different from those induced by diethylnitrosamine (DEN), a genotoxic hepatocarcinogen. Accordingly, we compared the cell kinetics of GST-P ⁺ foci after cessation of DEN treatment and performed comprehensive gene expression in DEN- or furan-induced GST-P ⁺ foci. The number and area of DEN-induced GST-P ⁺ foci were increased after cessation of treatment, whereas furan decreased these parameters. Size distribution analysis showed that large furan-induced GST-P ⁺ foci disappeared after cessation of treatment. Hierarchical cluster analysis showed that all samples from GST-P ⁺ foci induced by furan were separated from those induced by DEN. SOX9 expression was upregulated in furan-induced GST-P ⁺ foci and was detected by immunohistochemistry in large furan-induced GST-P ⁺ foci. Our results indicated that large furan-induced GST-P ⁺ foci were quite different from DEN-induced GST-P ⁺ foci at the molecular and cellular levels. And one of the properties of disappearing large GST-P ⁺ foci were characterized by inclusion of hepatocytes expressing SOX9.