HYDROGEN-PEROXIDE INHIBITS GAP JUNCTIONAL INTERCELLULAR COMMUNICATIONIN GLUTATHIONE SUFFICIENT BUT NOT GLUTATHIONE DEFICIENT CELLS

Cell to cell communication via gap junctions is essential in the maint enance of the homeostatic balance of multicellular organisms, Aberrant intercellular gap junctional communication (GJIC) has been implicated in tumor promotion, neuropathy and teratogenesis, Oxidative stress ha s also been implicated in similar pathologies such as cancer, We repor t a potential link between oxidative stress and GJIC, Hydrogen peroxid e, a known tumor promoter, inhibited GJIC in WB-F344 rat liver epithel ial cells with an I-50 value of 200 mu M. Inhibition of GJIC by H2O2 w as reversible as indicated by the complete recovery of GJIC with the r emoval of H2O2 via a change of fresh media, Free radical scavengers, s uch as t-butyl alcohol, propyl-gallate, and Trolox(R), did not prevent the inhibition of GJIC by H2O2, which indicated that the effects of H 2O2 on GJIC was probably not a consequence of aqueous free radical dam age, The depletion of intracellular GSH reversed the inhibitory effect of H2O2 on GJIC, The treatment of glutathione-sufficient cells with H 2O2 resulted in the hyperphosphorylation of connexin43, which is the b asic subunit of the hexameric gap junction protein, as determined by W estern blot analysis, TPA, a well-known tumor promoter, also inhibits GJIC via hyperphosphorylation of GJIC, which is a result of protein ki nase-C activation, However, H2O2 also induced hyperphosphorylation in GSH-deficient cells that had normal rates of GJIC, Therefore, the mech anism of GJIC inhibition must be different from the TPA-pathway and in volves GSH.