Source:http://linkedlifedata.com/resource/pubmed/id/16870158
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
7
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| pubmed:dateCreated |
2006-9-4
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| pubmed:abstractText |
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.
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| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
IM
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| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/1,7-dimethylxanthine,
http://linkedlifedata.com/resource/pubmed/chemical/5,5-dimethyl-1-pyrroline-1-oxide,
http://linkedlifedata.com/resource/pubmed/chemical/Adenosine Diphosphate,
http://linkedlifedata.com/resource/pubmed/chemical/Adenosine Triphosphate,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclic N-Oxides,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Hydrogen Peroxide,
http://linkedlifedata.com/resource/pubmed/chemical/NAD,
http://linkedlifedata.com/resource/pubmed/chemical/Nuclear Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/PARP1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Poly(ADP-ribose) Polymerases,
http://linkedlifedata.com/resource/pubmed/chemical/Theophylline,
http://linkedlifedata.com/resource/pubmed/chemical/Xanthines
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| pubmed:status |
MEDLINE
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| pubmed:month |
Sep
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| pubmed:issn |
0006-2952
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| pubmed:author | |
| pubmed:issnType |
Print
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| pubmed:day |
28
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| pubmed:volume |
72
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| pubmed:owner |
NLM
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| pubmed:authorsComplete |
Y
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| pubmed:pagination |
902-10
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| pubmed:dateRevised |
2006-11-15
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| pubmed:meshHeading |
pubmed-meshheading:16870158-Adenosine Diphosphate,
pubmed-meshheading:16870158-Adenosine Triphosphate,
pubmed-meshheading:16870158-Cell Line, Tumor,
pubmed-meshheading:16870158-Cell Survival,
pubmed-meshheading:16870158-Cyclic N-Oxides,
pubmed-meshheading:16870158-Dose-Response Relationship, Drug,
pubmed-meshheading:16870158-Electron Spin Resonance Spectroscopy,
pubmed-meshheading:16870158-Endothelial Cells,
pubmed-meshheading:16870158-Enzyme Inhibitors,
pubmed-meshheading:16870158-Enzyme-Linked Immunosorbent Assay,
pubmed-meshheading:16870158-Humans,
pubmed-meshheading:16870158-Hydrogen Peroxide,
pubmed-meshheading:16870158-Inhibitory Concentration 50,
pubmed-meshheading:16870158-Molecular Structure,
pubmed-meshheading:16870158-NAD,
pubmed-meshheading:16870158-Nuclear Proteins,
pubmed-meshheading:16870158-Oxidative Stress,
pubmed-meshheading:16870158-Poly(ADP-ribose) Polymerases,
pubmed-meshheading:16870158-Spin Trapping,
pubmed-meshheading:16870158-Structure-Activity Relationship,
pubmed-meshheading:16870158-Theophylline,
pubmed-meshheading:16870158-Xanthines
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| pubmed:year |
2006
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| pubmed:articleTitle |
Caffeine metabolites are inhibitors of the nuclear enzyme poly(ADP-ribose)polymerase-1 at physiological concentrations.
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| pubmed:affiliation |
Department of Pharmacology and Toxicology, Faculty of Medicine, University of Maastricht, PO Box 616, 6200 MD Maastricht, The Netherlands. l.geraets@farmaco.unimaas.nl
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| pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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