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Inotek Corporation, Beverly, Massachusetts 01915, USA
1Correspondence: Inotek Corporation, 100 Cummings Center, Suite 419E, Beverly, MA 01915, USA. E-mail: szabocsaba{at}aol.com
Purines such as adenosine, inosine, and hypoxanthine are known to
have potent antiinflammatory effects. These effects generally are
believed to be mediated by cell surface adenosine receptors. Here we
provide evidence that purines protect against oxidant-induced cell
injury by inhibiting the activation of the nuclear enzyme
poly(ADP-ribose) polymerase (PARP). Upon binding to broken DNA, PARP
cleaves NAD+ into nicotinamide and ADP-ribose and
polymerizes the latter on nuclear acceptor proteins such as histones
and PARP itself. Overactivation of PARP depletes cellular
NAD+ and ATP stores and causes necrotic cell death. We have
identified some purines (hypoxanthine, inosine, and adenosine) as
potential endogenous PARP inhibitors. We have found that purines
(hypoxanthine > inosine > adenosine) dose-dependently
inhibited PARP activation in peroxynitrite-treated macrophages and also
inhibited the activity of the purified PARP enzyme. Consistently with
their PARP inhibitory effects, the purines also protected interferon
+ endotoxin (IFN/LPS) -stimulated RAW macrophages from the
inhibition of mitochondrial respiration and inhibited nitrite
production from IFN/LPS-stimulated macrophages. We have selected
hypoxanthine as the most potent cytoprotective agent and PARP inhibitor
among the three purine compounds, and investigated the mechanism of its
cytoprotective effect. We have found that hypoxanthine protects
thymocytes from death induced by the cytotoxic oxidant peroxynitrite.
In line with the PARP inhibitory effect of purines, hypoxanthine has
prevented necrotic cell death while increasing caspase activity and DNA
fragmentation. As previously shown with other PARP inhibitors,
hypoxanthine acted proximal to mitochondrial alterations as
hypoxanthine inhibited the peroxynitrite-induced mitochondrial
depolarization and secondary superoxide production. Our data imply that
purines may serve as endogenous PARP inhibitors. We propose that, by
affecting PARP activation, purines may modulate the pattern of cell
death during shock, inflammation, and reperfusion injury.—Virág,
L., Szabó, C. Purines inhibit poly(ADP-ribose) polymerase
activation and modulate oxidant-induced cell death.
Key Words: nitric oxide • free radicals • antioxidants • shock • knockout • ADP-RT
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