TY - JOUR
T1 - Theophylline prevents NAD(+) depletion via PARP-1 inhibition in human pulmonary epithelial cells
AU - Moonen, H.J.
AU - Geraets, L.
AU - Vaarhorst, A.
AU - Bast, A.
AU - Wouters, E.F.
AU - Hageman, G.J.
PY - 2005/1/1
Y1 - 2005/1/1
N2 - 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.
AB - 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.
U2 - 10.1016/j.bbrc.2005.10.159
DO - 10.1016/j.bbrc.2005.10.159
M3 - Article
C2 - 16289039
SN - 0006-291X
VL - 338
SP - 1805
EP - 1810
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 4
ER -