Tributyltin increases cytosolic free Ca super(2+) concentration in thymocytes by mobilizing intracellular Ca super(2+), activating a Ca super(2+) entry pathway, and inhibiting Ca super(2+) efflux

The immunotoxic environmental pollutant tri-n-butyltin (TBT) kills thymocytes by apoptosis through a mechanism that requires an increase in intracellular Ca super(2+) concentration. The addition of TBT (EC sub(50) = 2 mu M) to fura-2-loaded rat thymocytes resulted in a rapid and sustained increase in the cytosolic free Ca super(2+) concentration ((Ca super(2+)) sub(i)) to greater than 1 mu M. in nominally Ca super(2+)-free medium, TBT slightly but consistently increased thymocyte (Ca super(2+)) sub(i) by about 0.1 mu M. The subsequent restoration of CaCl sub(2) to the medium resulted in a sustained overshoot in (Ca super(2+)) sub(i); similarly, the addition of MnCl sub(2) produced a rapid decrease in the intracellular fura-2 fluorescence in thymocytes exposed to TBT. Our results show that TBT increases (Ca super(2+)) sub(i) in thymocytes by the combination of intracellular Ca super(2+) mobilization, stimulation of Ca super(2+) entry, and ability of TBT to apparently mobilize the tBuBHQ-sensitive intracellular Ca super(2+) store followed by Ca super(2+) and Mn super(2+) entry suggests that the TBT-induced (Ca super(2+)) sub(i) increase involves a capacitative type of Ca super(2+) entry.