The inositol 1,4,5-trisphosphate-generating agonist ATP enhances DNA cleavage induced by tert-butylhydroperoxide

In this paper we present experimental evidence indicating that DNA cleavage induced by tert-butylhydroperoxide in U937 cells can be enhanced via ATP-mediated activation of membrane receptors coupled with hydrolysis of phosphatidylinositol 4,5-bisphosphate. The mechanism whereby ATP exerts this effect involves release of Ca2+ from the inositol 1,4,5-trisphosphate (IP3)-sensitive stores, further release of the cation from the ryanodine receptor, mitochondrial clearance of the fraction of Ca2+ derived from the ryanodine receptor, and Ca2+-dependent mitochondrial formation of DNA-damaging species. IP3-generating agonists must therefore be considered as potential modulators of the genotoxic effects of tert-butylhydroperoxide. (C) 1998 Academic Press.