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.
Clementi
E
E
Istituto di Farmacologia e Farmacognosia, Università di Urbino, Italy.
Guidarelli
A
A
Cantoni
O
O
D000255:Adenosine Triphosphate / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000494:pharmacology; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism*; D007700:Kinetics; D007951:Leukemia, Myeloid; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010545:Peroxides / Q000494:pharmacology*; D017382:Reactive Oxygen Species; D012433:Ryanodine / Q000494:pharmacology; D019837:Ryanodine Receptor Calcium Release Channel / Q000502:physiology; D014407:Tumor Cells, Cultured; D020122:tert-Butylhydroperoxide
D004273:DNA, Neoplasm; D010545:Peroxides; D017382:Reactive Oxygen Species; D019837:Ryanodine Receptor Calcium Release Channel; D012433:Ryanodine; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; D015544:Inositol 1,4,5-Trisphosphate; D000255:Adenosine Triphosphate; D020122:tert-Butylhydroperoxide; D002118:Calcium