論文 - 詳細
| RRC ID | 42712 |
|---|---|
| 著者 | Geraets L, Moonen HJ, Wouters EF, Bast A, Hageman GJ. |
| タイトル | Caffeine metabolites are inhibitors of the nuclear enzyme poly(ADP-ribose)polymerase-1 at physiological concentrations. |
| ジャーナル | Biochem Pharmacol |
| 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. |
| 巻・号 | 72(7) |
| ページ | 902-10 |
| 公開日 | 2006-9-28 |
| DOI | 10.1016/j.bcp.2006.06.023 |
| PII | S0006-2952(06)00370-4 |
| PMID | 16870158 |
| MeSH | 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* |
| IF | 4.96 |
| 引用数 | 67 |
| WOS 分野 | PHARMACOLOGY & PHARMACY |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | Patent(IFI CLAIMS) |
| 各媒体での言及数の合計 | 3 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | 10H(RCB0705) |