Inhibition of poly(ADP-ribose) polymerization preserves the glutathione pool and reverses cytotoxicity in hydrogen peroxide-treated lymphocytes.
DNA damage caused by oxygen radicals activates poly(ADP-ribosyl) polymerase (pADPRP), a nuclear enzyme that utilizes NAD+ as substrate. It has been demonstrated that pharmacological inactivation of pADPRP rescues human lymphocytes damaged by oxygen radicals, but not those damaged by equitoxic doses of ionizing radiation. In the present paper we demonstrate that the NAD+ pool decreases after both damaging treatments and is preserved in a similar fashion by pADPRP inhibition. On the contrary, the ATP pool, cell energy charge and reduced thiols are decreased only by the administration of oxygen radicals, and are preserved if poly(ADP)ribosylation is inhibited. In fact, treatment with oxidant agents depletes the cell energy pools owing to the simultaneous demands of the glutathione (GSH)/NADPH cycle and pADPRP-driven NAD+ consumption, while in irradiated cells only the latter mechanism operates. We suggest that, when pADPRP is inhibited, enough energy is available for the preservation of cell thiols, thereby allowing oxidant-treated cells to survive and undergo mitosis. Thus, GSH and energy shortage appear to be the main cause of cell death in oxidant-injured cells.
Marini
M
M
Istituto di Istologia ed Embriologia Generale, Facoltà di Medicina, Università di Bologna, Italy.
Frabetti
F
F
Brunelli
M A
MA
Raggi
M A
MA
D000255:Adenosine Triphosphate / Q000378:metabolism; D000328:Adult; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000037:antagonists & inhibitors* / Q000633:toxicity; D008214:Lymphocytes / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects; D008297:Male; D008875:Middle Aged; D009243:NAD / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D017382:Reactive Oxygen Species / Q000494:pharmacology; D013438:Sulfhydryl Compounds / Q000378:metabolism
D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D017382:Reactive Oxygen Species; D013438:Sulfhydryl Compounds; D009243:NAD; D000255:Adenosine Triphosphate; D006861:Hydrogen Peroxide; D005978:Glutathione