Anti-inflammatory properties of anthraquinones and their relationship with the regulation of p-glycoprotein function and expression

被引:85
作者
Choi, Ran Joo [1 ]
Tran Minh Ngoc [2 ]
Bae, KiHwan [2 ]
Cho, Hyun-Jong [3 ,4 ,5 ]
Kim, Dae-Duk [3 ,4 ]
Chun, Jaemoo [1 ]
Khan, Salman [1 ]
Kim, Yeong Shik [1 ]
机构
[1] Seoul Natl Univ, Coll Pharm, Inst Nat Prod Res, Seoul 151742, South Korea
[2] Chungnam Natl Univ, Coll Pharm, Taejon 305764, South Korea
[3] Seoul Natl Univ, Coll Pharm, Seoul 151742, South Korea
[4] Seoul Natl Univ, Pharmaceut Sci Res Inst, Seoul 151742, South Korea
[5] Kangwon Natl Univ, Coll Pharm, Chunchon 200701, South Korea
基金
新加坡国家研究基金会;
关键词
Rhubarb; Anthraquinones; P-glycoprotein; COX-2; Anti-inflammatory; MULTIDRUG-RESISTANCE GENE; HERB-DRUG INTERACTIONS; IN-VITRO; INTESTINAL-ABSORPTION; INHIBITS MDR1; ALOE-EMODIN; TRANSPORT; CELLS; PERMEABILITY; MECHANISM;
D O I
10.1016/j.ejps.2012.10.027
中图分类号
R9 [药学];
学科分类号
100702 [药剂学];
摘要
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. (C) 2012 Elsevier B.V. All rights reserved.
引用
收藏
页码:272 / 281
页数:10
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