Caffeine metabolites are inhibitors of the nuclear enzyme poly(ADP-ribose)polymerase-1 at physiological concentrations

Biochem Pharmacol. 2006 Sep 28;72(7):902-10. doi: 10.1016/j.bcp.2006.06.023. Epub 2006 Jul 25.


The activity of the nuclear enzyme poly(ADP-ribose)polymerase-1 (E.C., which is highly activated by DNA strand breaks, is associated with the pathophysiology of both acute as well as chronic inflammatory diseases. PARP-1 overactivation and the subsequent extensive turnover of its substrate NAD+ put a large demand on mitochondrial ATP-production. Furthermore, due to its reported role in NF-kappaB and AP-1 mediated production of pro-inflammatory cytokines, PARP-1 is considered an interesting target in the treatment of these diseases. In this study the PARP-1 inhibiting capacity of caffeine and several metabolites as well as other (methyl)xanthines was tested using an ELISA-assay with purified human PARP-1. Caffeine itself showed only weak PARP-1 inhibiting activity, whereas the caffeine metabolites 1,7-dimethylxanthine, 3-methylxanthine and 1-methylxanthine, as well as theobromine and theophylline showed significant PARP-1 inhibiting activity. Further evaluation of these compounds in H2O2-treated A549 lung epithelial and RF24 vascular endothelial cells revealed that the decrease in NAD+-levels as well as the formation of the poly(ADP-ribose)polymer was significantly prevented by the major caffeine metabolite 1,7-dimethylxanthine. Furthermore, H2O2-induced necrosis could be prevented by a high dose of 1,7-dimethylxanthine. Finally, antioxidant effects of the methylxanthines could be ruled out with ESR and measurement of the TEAC. Concluding, caffeine metabolites are inhibitors of PARP-1 and the major caffeine metabolite 1,7-dimethylxanthine has significant PARP-1 inhibiting activity in cultured epithelial and endothelial cells at physiological concentrations. This inhibition could have important implications for nutritional treatment of acute and chronic inflammatory pathologies, like prevention of ischemia-reperfusion injury or vascular complications in diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Diphosphate / metabolism
  • Adenosine Triphosphate / metabolism
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cyclic N-Oxides / pharmacology
  • Dose-Response Relationship, Drug
  • Electron Spin Resonance Spectroscopy / methods
  • Endothelial Cells / cytology
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Enzyme-Linked Immunosorbent Assay / methods
  • Humans
  • Hydrogen Peroxide / pharmacology
  • Inhibitory Concentration 50
  • Molecular Structure
  • NAD / chemistry
  • NAD / metabolism
  • Nuclear Proteins / antagonists & inhibitors
  • Nuclear Proteins / metabolism
  • Oxidative Stress / drug effects
  • Oxidative Stress / physiology
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerase Inhibitors*
  • Poly(ADP-ribose) Polymerases / metabolism
  • Spin Trapping / methods
  • Structure-Activity Relationship
  • Theophylline / chemistry
  • Theophylline / pharmacology*
  • Xanthines / chemistry
  • Xanthines / pharmacology*


  • Cyclic N-Oxides
  • Enzyme Inhibitors
  • Nuclear Proteins
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Xanthines
  • NAD
  • Adenosine Diphosphate
  • 5,5-dimethyl-1-pyrroline-1-oxide
  • Adenosine Triphosphate
  • Hydrogen Peroxide
  • Theophylline
  • PARP1 protein, human
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases
  • 1,7-dimethylxanthine