title: Resveratrol as a Bioenhancer to Improve Anti-Inflammatory Activities of Apigenin.
abstract: The aim of this study was to improve the anti-inflammatory activities of apigenin through co-treatment with resveratrol as a bioenhancer of apigenin. RAW 264.7 cells pretreated with hepatic metabolites formed by the co-metabolism of apigenin and resveratrol (ARMs) in HepG2 cells were stimulated with lipopolysaccharide (LPS). ARMs prominently inhibited (p < 0.05) the production of nitric oxide (NO), prostaglandin E₂ (PGE₂), interleukin (IL)-1β, IL-6 and TNF-α. Otherwise no such activity was observed by hepatic metabolites of apigenin alone (AMs). ARMs also effectively suppressed protein expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Co-administration of apigenin (50 mg/kg) and resveratrol (25 mg/kg) also showed a significant reduction of carrageenan-induced paw edema in mice (61.20% to 23.81%). Co-administration of apigenin and resveratrol led to a 2.39 fold increase in plasma apigenin levels compared to administration of apigenin alone, suggesting that co-administration of resveratrol could increase bioavailability of apigenin. When the action of resveratrol on the main apigenin metabolizing enzymes, UDP-glucuronosyltransferases (UGTs), was investigated, resveratrol mainly inhibited the formation of apigenin glucuronides by UGT1A9 in a non-competitive manner with a Ki value of 7.782 μM. These results suggested that resveratrol helps apigenin to bypass hepatic metabolism and maintain apigenin's anti-inflammatory activities in the body.
authors.affiliation: Research Group of Nutraceuticals for Metabolic Syndrome, Korea Food Research Institute, 1201-62, Anyangpangyoro, Seongnam, Gyeonggi 463-746, Korea. 07636@kfri.re.kr.
authors.forename: Jin-Ah
authors.initials: JA
authors.lastname: Lee
authors.affiliation: Research Group of Nutraceuticals for Metabolic Syndrome, Korea Food Research Institute, 1201-62, Anyangpangyoro, Seongnam, Gyeonggi 463-746, Korea. skha@kfri.re.kr.
authors.forename: Sang Keun
authors.initials: SK
authors.lastname: Ha
authors.affiliation: Research Group of Nutraceuticals for Metabolic Syndrome, Korea Food Research Institute, 1201-62, Anyangpangyoro, Seongnam, Gyeonggi 463-746, Korea. Cho.Eun-jung@kfri.re.kr.
authors.forename: EunJung
authors.initials: E
authors.lastname: Cho
authors.affiliation: Research Group of Nutraceuticals for Metabolic Syndrome, Korea Food Research Institute, 1201-62, Anyangpangyoro, Seongnam, Gyeonggi 463-746, Korea. choiw@kfri.re.kr.
authors.forename: Inwook
authors.initials: I
authors.lastname: Choi
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D047310:Apigenin / Q000097:blood / Q000494:pharmacology*; D002351:Carrageenan / Q000008:administration & dosage / Q000633:toxicity; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004357:Drug Synergism; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D014453:Glucuronosyltransferase / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D000067996:RAW 264.7 Cells; D000077185:Resveratrol; D013267:Stilbenes / Q000097:blood / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D053583:Interleukin-1beta; D015850:Interleukin-6; D008070:Lipopolysaccharides; D013267:Stilbenes; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D047310:Apigenin; D002351:Carrageenan; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D014453:Glucuronosyltransferase; D015232:Dinoprostone; D000077185:Resveratrol
keywords: UDP-glucuronosyltransferase (UGT); anti-inflammation; bioenhancer; hepatic metabolites of apigenin