Exposure to 12-O-tetradecanoylphorbol-13-acetate (TPA) has been shown to inhibit gap junctional intercellular communication (GJIC) in many cell types in vitro. Using a scrape loading/dye transfer technique, TPA was shown to cause a dose-dependent and transient inhibition of GJIC in WB-F344, a normal rat liver epithelial cell line. Such a down-modulation of intercellular communication was found to be associated with an increase in protein kinase C (PKC) activity. Translocation of this activity to the particulate fraction occurred 10 min after exposure to 16 nM TPA and was consistent with the time course needed to inhibit GJIC. After 6 h exposure to TPA, essentially all the PKC activity was lost concurrent with the recovery of communication in these cells. During this time, the cells also became refractory to inhibition by further addition of TPA. Blockage of communication induced by TPA in WB cells was prevented by treating the cells with 23 microM palmitoyl carnitine for 1 h or 100 microM 8-N, N-(diethylamino)-octyl-3,4, 5-trimethoxybenzoate for 30 min. The results indicate that TPA transiently modulates GJIC in WB cells and PKC activation is possibly involved in blockage of communication in these cells.