Caspase involvement in the induction of apoptosis by the environmental toxicants tributyltin and triphenyltin

Organotin compounds such as tributyltin (TBT) and triphenyltin (TPT) can ki ll target cells by triggering apoptosis. The mechanism by which these envir onmental toxicants activate the apoptotic program is currently unclear, We have studied the effect of TBT and TPT in the human Hut-78 and Jurkat T-lym phocyte cell lines. Within 1 h there was a 30-fold increase in caspase acti vity, as measured by the cleavage of the fluorescent peptide DEVD-AMC. Morp hological changes characteristic of apoptosis, such as membrane blebbing an d nuclear fragmentation, were readily detectable. Blocking caspase activity with the peptide inhibitor z-VAD-fmk prevented all subsequent apoptotic ch anges. The optimal concentration range for induction of apoptosis was 0.5 t o 5 mu M TBT. TPT was also able to trigger caspase activity in the lymphocy te cell lines, but it took over 2 h to detect and occurred at a lower conce ntration range of 0.01 to 1 mu M. Higher concentrations of TBT and TPT caus ed cell necrosis, and we showed that these concentrations were able to inhi bit caspase activity in apoptotic cells. TBT and TPT were able interact wit h a vicinal thiol compound, similar to the known caspase inhibitor phenylar sine oxide, providing a potential mechanism for caspase inhibition. We prop ose that vicinal thiol proteins may be a general biological target of these organotin compounds, leading to the induction of caspase activity and apop tosis at low concentrations, and more extensive cell damage and necrotic ce ll death at higher concentrations. (C) 1999 Academic Press.