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.
|Journal||Biochemical and Biophysical Research Communications|
|Publication status||Published - 1 Jan 2005|
Moonen, H. J., Geraets, L., Vaarhorst, A., Bast, A., Wouters, E. F., & Hageman, G. J. (2005). Theophylline prevents NAD(+) depletion via PARP-1 inhibition in human pulmonary epithelial cells. Biochemical and Biophysical Research Communications, 338(4), 1805-1810. https://doi.org/10.1016/j.bbrc.2005.10.159