Molecular mechanisms of gastrointestinal protection by quercetin against indomethacin-induced damage: role of NF-κB and Nrf2.
The aim of this study was to determine the gastrointestinal protection by quercetin against indomethacin-induced oxidative stress and inflammation, with specific interest in studying the underlying molecular mechanisms. We hypothesized that the quercetin-protective effect relies on its antioxidant and antiinflammatory properties. Rats were pretreated with quercetin (50- or 100-mg/kg, ig single dose), 30 min before INDO administration (40-mg/kg ig single dose). Caco-2 cells were treated with INDO (250 and 500 μM) in the absence or presence of quercetin (10 μg/ml). Quercetin prevented the decrease in nuclear translocation of Nrf2, a key regulator of the antioxidant response, and the increase in reactive oxygen species levels induced by INDO by inhibiting the enhancement of NADPH oxidase and xanthine oxidase activities as well as the reduction in superoxide dismutase and glutathione peroxidase activities in gastric and ileal tissues. Quercetin also prevented INDO-induced ICAM-1 and P-selectin expressions and the increase of myeloperoxidase activity in gastric and ileal tissues and NF-κB activation and IL-8 production in Caco-2 cells. Quercetin did not affect the inhibition of TNFα-mediated production of prostaglandin E2 induced by INDO in Caco-2 cells. The protective effects of quercetin observed in the gastric and ileal mucosa of rats as well as in Caco-2 cells relied on the ability of this flavonol to prevent NF-κB activation and increase Nrf2 translocation. This study supports the concept that quercetin may be useful in the prevention and/or treatment of nonsteroidal antiinflammatory drug-associated side effects, without interfering with their therapeutic efficacy.
Department of Nutrition, Faculty of Medicine, University of Chile, Av. Independencia 1027, Santiago, Chile, P.O. Box 8380453. Electronic address: catalinacarrasco@med.uchile.cl.
Catalina
C
Carrasco-Pozo
Pathophysiology Program, Faculty of Medicine, University of Chile, Av. Independencia 1027, Santiago, Chile, P.O. Box 8380453.
Rodrigo L
RL
Castillo
Laboratory of Immunogastroenterology, Division of Gastroenterology, Hospital Clínico Universidad de Chile, Santos Dumont 999, Independencia, Santiago, Chile, P.O. Box, 8380456.
Caroll
C
Beltrán
Laboratory of Immunogastroenterology, Division of Gastroenterology, Hospital Clínico Universidad de Chile, Santos Dumont 999, Independencia, Santiago, Chile, P.O. Box, 8380456.
Alfonso
A
Miranda
Institute of Nutrition and Food Technology, University of Chile, Av. Macul 5540, Santiago, Chile, P.O. Box 138-11.
Jocelyn
J
Fuentes
Department of Nutrition, Faculty of Medicine, University of Chile, Av. Independencia 1027, Santiago, Chile, P.O. Box 8380453; Institute of Nutrition and Food Technology, University of Chile, Av. Macul 5540, Santiago, Chile, P.O. Box 138-11.
Martin
M
Gotteland
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity*; D018938:Caco-2 Cells; D041981:Gastrointestinal Tract / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007213:Indomethacin / Q000633:toxicity*; D008297:Male; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D011794:Quercetin / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000894:Anti-Inflammatory Agents, Non-Steroidal; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495637:Nfe2l2 protein, rat; D011794:Quercetin; D007213:Indomethacin
Indomethacin; Inflammation; NF-kB; Nrf2; Oxidative stress; Quercetin