Some phenol derivatives are known to block volume-sensitive Cl(-) channels. However, effects on the channel of the bisphenol phloretin, which is a known blocker of glucose uniport and anion antiport, have not been examined. In the present study, we investigated the effects of phloretin on volume-sensitive Cl(-) channels in comparison with cyclic AMP-activated CFTR Cl(-) channels and Ca(2+)-activated Cl(-) channels using the whole-cell patch-clamp technique. Extracellular application of phloretin (over 10 microM) voltage-independently, and in a concentration-dependent manner (IC(50) approximately 30 microM), inhibited the Cl(-) current activated by a hypotonic challenge in human epithelial T84, Intestine 407 cells and mouse mammary C127/CFTR cells. In contrast, at 30 microM phloretin failed to inhibit cyclic AMP-activated Cl(-) currents in T84 and C127/CFTR cells. Higher concentrations (over 100 microM) of phloretin, however, partially inhibited the CFTR Cl(-) currents in a voltage-dependent manner. At 30 and 300 microM, phloretin showed no inhibitory effect on Ca(2+)-dependent Cl(-) currents induced by ionomycin in T84 cells. It is concluded that phloretin preferentially blocks volume-sensitive Cl(-) channels at low concentrations (below 100 microM) and also inhibits cyclic AMP-activated Cl(-) channels at higher concentrations, whereas phloretin does not inhibit Ca(2+)-activated Cl(-) channels in epithelial cells.