INHIBITORY EFFECTS OF ENDOSULFAN ON GAP JUNCTIONAL INTERCELLULAR COMMUNICATION IN WB-F344 RAT-LIVER CELLS AND PRIMARY RAT HEPATOCYTES

The chlorinated cyclodiene insecticide endosulfan is a potent inhibitor of gap junctional intercellular communication (GJIC) in vitro, a property shared by many tumour promoters and suggested to indicate an intrinsic tumour-promoting potential. However, endosulfan did not act as a tumour promoter in an altered hepatic foci assay in the rat in vivo, and ambiguous results regarding the carcinogenic potential of endosulfan have emerged from long-term studies in rodents. In the present study the GJIC-inhibitory potentials of the two isomers of endosulfan were investigated in WB-F344 rat liver epithelial cells and primary rat hepatocytes. The results show that both isomers are inhibitors of GJIC. However, beta-endosulfan (ENDO-beta) is a more potent inhibitor of GJIC in primary rat hepatocytes than alpha-endosulfan (ENDO-alpha), whereas the two isomers were equally potent as inhibitors of GJIC in WB-F344 rat liver cells. In primary rat hepatocytes membrane-permeant dibutyryl cyclic AMP (dB-cAMP) counteracts the inhibitory effect of ENDO-beta without affecting the effect of ENDO-alpha. However, in WB-F344 rat liver cells dB-cAMP failed to prevent the inhibitory effects of either ENDO-alpha or ENDO-beta. In addition, studies in WB-F344 rat liver cells show that ENDO-alpha-beta does not decrease the intracellular cAMP concentration. Thus, it is unlikely that ENDO-alpha-beta or its isomers and metabolites inhibit GJIC by lowering the intracellular cAMP concentration. Furthermore, comparison of the effective doses and recovery times imply that GJIC in WB-F344 rat liver cells is more sensitive to treatment by ENDO-alpha-beta, its isomers and metabolites than GJIC in primary rat hepatocytes. Thus, the present results demonstrate significant differences between primary rat hepatocytes and WB-F344 rat liver cells in the response of their GJIC to endosulfan.