title: Anti-inflammatory properties of anthraquinones and their relationship with the regulation of P-glycoprotein function and expression.
abstract: There is a growing interest in natural products that potentially have anti-inflammatory properties and inhibit P-glycoprotein (P-gp) function. In this report, we assessed the effects of anthraquinone derivatives from rhubarb on LPS-induced RAW 264.7 macrophages to determine their anti-inflammatory potential. The derivatives were also tested in Caco-2 cell lines to evaluate the inhibition of the drug efflux function of P-gp. The transport abilities were examined and the cellular accumulation of rhodamine-123 (R-123) was also measured. Electorphoretic mobility shift assay (EMSA) was performed to check the activator protein-1 (AP-1) DNA binding affinity. Five anthraquinones were tested to determine their inhibitory activities on NO production and the protein and mRNA expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Furthermore, the level of prostaglandin E(2) (PGE(2)) was determined in LPS-induced RAW264.7 macrophages. Emodin was found to be the most potent inhibitor, and it also reduced paw swelling in the mouse model of carrageenan-induced paw edema. In Caco-2 cells, emodin elevated the accumulation of R-123 and decreased the efflux ratio of R-123, which indicates the inhibition of P-gp function. The inhibition of COX-2 protein by emodin paralleled the decrease in P-gp expression. In addition, mitogen-activated protein kinase (MAPK) expression was decreased through the prevention of AP-1 DNA binding, which leads to downregulation in the expression of P-gp. Our data indicate that the decrease of P-gp expression is caused by the decreased expression of COX-2 through the MAPK/AP-1 pathway. Based on our results, we suggest that anti-inflammatory drugs with COX-2 inhibitory activity might be used to modulate P-gp function and expression.
authors.affiliation: Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Ran Joo
authors.initials: RJ
authors.lastname: Choi
authors.forename: Tran Minh
authors.initials: TM
authors.lastname: Ngoc
authors.forename: Kihwan
authors.initials: K
authors.lastname: Bae
authors.forename: Hyun-Jong
authors.initials: HJ
authors.lastname: Cho
authors.forename: Dae-Duk
authors.initials: DD
authors.lastname: Kim
authors.forename: Jaemoo
authors.initials: J
authors.lastname: Chun
authors.forename: Salman
authors.initials: S
authors.lastname: Khan
authors.forename: Yeong Shik
authors.initials: YS
authors.lastname: Kim
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D000880:Anthraquinones / Q000494:pharmacology / Q000627:therapeutic use*; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D018938:Caco-2 Cells; D002351:Carrageenan; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000235:genetics; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D015232:Dinoprostone / Q000378:metabolism; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D008517:Phytotherapy; D010936:Plant Extracts / Q000494:pharmacology / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D012250:Rheum; D027343:Rhizome
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000880:Anthraquinones; D000893:Anti-Inflammatory Agents; D052246:Cyclooxygenase 2 Inhibitors; D010936:Plant Extracts; D012333:RNA, Messenger; D009569:Nitric Oxide; D002351:Carrageenan; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D015232:Dinoprostone