Abstract
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.
MeSH terms
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Adenosine Triphosphate / pharmacology*
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Calcium / metabolism
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Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / pharmacology
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DNA Damage*
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DNA, Neoplasm / drug effects*
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DNA, Neoplasm / metabolism
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Humans
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Inositol 1,4,5-Trisphosphate / metabolism*
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Kinetics
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Leukemia, Myeloid
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Mitochondria / drug effects
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Mitochondria / metabolism
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Peroxides / pharmacology*
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Reactive Oxygen Species
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Ryanodine / pharmacology
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Ryanodine Receptor Calcium Release Channel / physiology
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Tumor Cells, Cultured
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tert-Butylhydroperoxide
Substances
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DNA, Neoplasm
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Peroxides
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Reactive Oxygen Species
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Ryanodine Receptor Calcium Release Channel
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Ryanodine
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Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone
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Inositol 1,4,5-Trisphosphate
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Adenosine Triphosphate
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tert-Butylhydroperoxide
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Calcium