Comparative effects of phenobarbital, DDT, and lindane on mouse hepatocyte gap junctional intercellular communication

Abstract

Gap junctional intercellular communication appears to be important in the regulation of cellular homeostasis, differentiated cell functions, and growth control in adult tissues. Interruption of intercellular communication by chemical compounds has been shown to be a sublethal response to a number of tumor promoters. The mechanism by which tumor promoters inhibit intercellular communication remains unresolved. In the present study the kinetics of inhibition of mouse hepatocyte gap junctional intercellular communication (measured by dye coupling) by three well-established hepatic tumor promoters [phenobarbital, 1,1-bis(4-chlorophenyl)-2,2,2-trichloroethane (DDT), and gamma-hexachlorocyclohexane (lindane)] are compared. All three compounds inhibited intercellular communication in a time- and dose-dependent manner in both freshly plated and 24-hr-old hepatocyte cultures. Following removal of the tumor promoters from the culture medium, intercellular communication was reestablished within 0.5 hr (phenobarbital) to 1.5 hr (DDT and lindane). Prolonged treatment of hepatocytes for up to 48 hr with the three promoters resulted in the continued inhibition of intercellular communication by lindane and DDT, but the development of refractoriness to phenobarbital-induced inhibition of intercellular communication. Concomitant treatment with combinations of the three promoters showed an additive effect of the compounds on inhibition of intercellular communication. Inhibition of intercellular communication by phenobarbital was prevented by addition of the cytochrome P450 enzyme inhibitor SKF-525A. SKF-525A had no effect on the inhibition of intercellular communication induced by lindane or DDT. Coincubation of the three promoters with the cAMP analog 8-bromo-cAMP prevented the promoter-induced inhibition of intercellular communication.