MODIFICATION OF CYTOSOLIC-FREE CALCIUM CONCENTRATIONS IN HUMAN KERATINOCYTES AFTER SULFUR MUSTARD EXPOSURE

Exposure of confluent cultures of human skin keratinocytes sulfur must ard (SM) induced an immediate and irreversible rise in internal free C a2+ levels that was independent of external Ca2+ concentrations. The r esponse was rapid, beginning within 1 min after addition of SM to the cells, and sensitive, with significant effects observed at 100 mu M. T he rise in [Ca2+]INT was unaffected by zero external Ca2+ but was bloc ked by prior incubation with thapsigargin. The sensitivity to and irre versibility of the effects of SM on Ca2+ levels was paralleled by cell ular toxicity as assessed using three different cell viability assays. In addition, the time course of the onset of irreversible toxicity in our cultures coincides with the time course of effects on [Ca2+]INT. SM was also Found to displace specifically bound ATP from purinergic ( P-2) receptors. These results suggest that therapies aimed at protecti ng internal stores of Ca2+ from disruption by SM, perhaps at P-2 recep tors, may provide substantial benefit in protecting human skin cells f rom the toxic effects of this vesicant. (C) 1998 Elsevier Science Ltd. All rights reserved.