title: The O-methylation of chrysin markedly improves its intestinal anti-inflammatory properties: Structure-activity relationships of flavones.
abstract: The aim of this study was to investigate whether methoxylated flavones versus their unmethylated analogs can modulate the intestinal inflammatory response. Flavone effects were assessed on soluble pro-inflammatory mediator (IL-8, IL-6, macrophage chemoattractant protein-1 (MCP-1), and cyclooxygenase-2 (COX-2)-derived PGE2) production and on nuclear factor (NF)-κB activation in 3d-confluent and 21d-differentiated Caco-2 cells stimulated with interleukin (IL)-1β. Chrysin (CHRY) showed anti-inflammatory properties by decreasing COX-2-derived PGE2 and reducing NF-κB activation. Compared to CHRY, the dimethoxylated form (CHRY-DM) significantly reduced the secretion of all pro-inflammatory mediators, except IL-8, at both cellular stages (P<0.05); these effects being dose-dependent in 3d-cells. The reduction of NF-κB activation was significantly more pronounced with CHRY-DM. By evaluating other flavones, it was established that several structural dispositions of flavones seemed to be determinant in order to attenuate the intestinal inflammatory response, such as methoxylation of the 5- and 7-hydroxyl groups on the A-ring, non-methoxylation of the 3'-hydroxyl groups on the B-ring, and methoxylation of the 3-hydroxyl group on the C-ring. Of all flavones examined, CHRY-DM exhibited the strongest anti-inflammatory activity. These data indicate that, in the Caco-2 cell model, methoxylation of CHRY greatly improves its anti-inflammatory properties, probably through a more pronounced inhibition of the NF-κB signaling pathway. Nevertheless, methoxylation of other flavones was not systematically beneficial.
authors.affiliation: Institut des Sciences de la Vie, UCLouvain, B 1348 Louvain-la-Neuve, Belgium. Electronic address: alexandrine.during@univ-lille2.fr.
authors.forename: Alexandrine
authors.initials: A
authors.lastname: During
authors.forename: Yvan
authors.initials: Y
authors.lastname: Larondelle
mesh_terms: D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology*; D018938:Caco-2 Cells; D004305:Dose-Response Relationship, Drug; D047309:Flavones / Q000737:chemistry / Q000494:pharmacology*; D005419:Flavonoids / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects*; D008745:Methylation; D016328:NF-kappa B / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000893:Anti-Inflammatory Agents; D047309:Flavones; D005419:Flavonoids; D018836:Inflammation Mediators; D016328:NF-kappa B; C043561:chrysin
keywords: 3′,4′,3,5,7-pentamethoxyflavone; 3′,4′,3,5,7-pentamethoxyflavone (PubChem CID 97332); 3′,4′,5,7-tetramethoxyflavone; 3′,4′,5,7-tetramethoxyflavone (PubChem CID 631170); 3′,4′-DHF; 3′,4′-DMF; 3′,4′-dihydroxyflavone; 3′,4′-dihydroxyflavone (PubChem CID 145726); 3′,4′-dimethoxyflavone; 3′,4′-dimethoxyflavone (PubChem CID 688674); 4′,5,7-trimethoxyflavone; 4′,5,7-trimethoxyflavone (PubChem CID 79730); 5,7-dimethoxyflavone (PubChem CID 88881); API; API-TM; CHRY; CHRY-DM; COMT; COX; CTL; Caco-2 cells; Chrysin (PubChem CID 5281607); DSS; FBS; Flavones; IBDs; IECs; IL; Intestinal inflammation; LDH; LPS; LUT; LUT-QM; MCP-1; NEAA; NF-κB; O-methylation; Pro-inflammatory mediators; QUER; QUER-PM; apigenin (PubChem CID 5280443); apigenin or 4′,5,7-trihydroxyflavone; catechol-O-methyltransferase; chrysin or 5,7-dihydroxyflavone; control; cyclooxygenase; dextran sodium sulfate; dimethylated chrysin or 5,7-dimethoxyflavone; fetal bovine serum; iNOS; inducible nitric oxide synthase; interleukin; intestinal bowel diseases; intestinal epithelial cells; lactate dehydrogenase; lipopolysaccharide; luteolin (PubChem CID 5280445); luteolin or 3′,4′,5,7-tetrahydroxyflavone; monocyte chemotactic protein-1; nonessential amino acids; nuclear factor κB; quercetin (PubChem CID 5280343); quercetin or 3′,4′,3,5,7-pentahydroxyflavone