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

Abstract

The activity of the nuclear enzyme poly(ADP-ribose)polymerase-1 (E.C.2.4.2.30), 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.

• Authors: Liesbeth Geraets, Harald J J Moonen, Emiel F M Wouters, Aalt Bast, Geja J Hageman
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 72 Issue 7 Pg. 902-10 (Sep 28 2006) ISSN: 0006-2952 [Print] England
• PMID: 16870158 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• 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, drug effects, metabolism)
• Enzyme Inhibitors (chemistry, pharmacology)
• Enzyme-Linked Immunosorbent Assay (methods)
• Humans
• Hydrogen Peroxide (pharmacology)
• Inhibitory Concentration 50
• Molecular Structure
• NAD (chemistry, metabolism)
• Nuclear Proteins (antagonists & inhibitors, metabolism)
• Oxidative Stress (drug effects, physiology)
• Poly (ADP-Ribose) Polymerase-1
• Poly(ADP-ribose) Polymerase Inhibitors
• Poly(ADP-ribose) Polymerases (metabolism)
• Spin Trapping (methods)
• Structure-Activity Relationship
• Theophylline (chemistry, pharmacology)
• Xanthines (chemistry, pharmacology)