Dietary flavones and flavonoles are inhibitors of poly(ADP-ribose)polymerase-1 in pulmonary epithelial cells.
The nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1), which was initially known to be highly activated by oxidative stress-induced DNA strand breaks, has been shown to be involved in the pathophysiology of acute and chronic inflammatory diseases. PARP-1 deficiency in mice led to the discovery of its coactivating function in the nuclear factor-kappa B-mediated gene expression and in addition, pharmaceutical inhibition of PARP-1 was shown to reduce the production of inflammatory mediators. In this study, the in vitro PARP-1-inhibiting effect of various flavonoids was investigated. The flavonoids myricetin, tricetin, gossypetin, delphinidin, quercetin, and fisetin were identified as significant inhibitors of the purified enzyme. Further evaluation of these compounds in N-methyl-N'-nitro-N-nitrosoguanidine-treated human pulmonary epithelial cells showed that the formation of the poly(ADP-ribose) polymers, as well as the decreased NAD(+) levels, was reduced by quercetin, fisetin, and tricetin. Finally, IL-8 production of LPS-stimulated human pulmonary epithelial cells could be significantly reduced by these flavonoids. The results of this study indicate that specific flavonoids have PARP-1-inhibiting activity in addition to the earlier described antioxidant effects. PARP-1 inhibition and preservation of cellular NAD(+) and energy production could play a role in the antiinflammatory activity of these specific flavonoids. In addition, these results indicate additional mechanisms by which flavonoids can exert antiinflammatory activity. Furthermore, these results indicate possibilities to use food-derived flavonoids in the treatment of chronic inflammatory diseases.
Geraets
Liesbeth
L
Department of Pharmacology and Toxicology, Maastricht University, 6200 MD Maastricht, The Netherlands. l.geraets@farmaco.unimaas.nl
Moonen
Harald J J
HJ
Brauers
Karen
K
Wouters
Emiel F M
EF
Bast
Aalt
A
Hageman
Geja J
GJ
D045744:Cell Line, Tumor; D004032:Diet; D047309:Flavones / Q000494:pharmacology*; D044948:Flavonols / Q000494:pharmacology*; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000378:metabolism; D008769:Methylnitronitrosoguanidine / Q000494:pharmacology; D009243:NAD / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D020545:Respiratory Mucosa / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism
D047309:Flavones; D044948:Flavonols; D016209:Interleukin-8; D016328:NF-kappa B; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D009243:NAD; D008769:Methylnitronitrosoguanidine; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1