Theophylline prevents NAD+ depletion via PARP-1 inhibition in human pulmonary epithelial cells.
Oxidative DNA damage, as occurs during exacerbations in chronic obstructive pulmonary disease (COPD), highly activates the nuclear enzyme poly(ADP-ribose)polymerase-1 (PARP-1). This can lead to cellular depletion of its substrate NAD+, resulting in an energy crisis and ultimately in cell death. Inhibition of PARP-1 results in preservation of the intracellular NAD+ pool, and of NAD+-dependent cellular processes. In this study, PARP-1 activation by hydrogen peroxide decreased intracellular NAD+ levels in human pulmonary epithelial cells, which was found to be prevented in a dose-dependent manner by theophylline, a widely used compound in the treatment of COPD. This enzyme inhibition by theophylline was confirmed in an ELISA using purified human PARP-1 and was found to be competitive by nature. These findings provide new mechanistic insights into the therapeutic effect of theophylline in oxidative stress-induced lung pathologies.
Moonen
Harald J J
HJ
Department of Health Risk Analysis and Toxicology, University of Maastricht, Maastricht, The Netherlands. h.moonen@grat.unimaas.nl
Geraets
Liesbeth
L
Vaarhorst
Anika
A
Bast
Aalt
A
Wouters
Emiel F M
EF
Hageman
Geja J
GJ
D045744:Cell Line, Tumor; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007700:Kinetics; D008168:Lung / Q000166:cytology / Q000378:metabolism*; D009243:NAD / Q000378:metabolism*; D018384:Oxidative Stress; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy; D013806:Theophylline / Q000494:pharmacology* / Q000627:therapeutic use
D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D009243:NAD; D006861:Hydrogen Peroxide; D013806:Theophylline; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1