title: Regulation of P-glycoprotein efflux activity by Z-guggulsterone of Commiphora mukul at the blood-brain barrier.
abstract: The present study was to investigate whether Z-guggulsterone had the regulatory effect on the activity and expression of P-glycoprotein in rat brain microvessel endothelial cells (rBMECs) and in rat brain. Inorganic phosphate liberation assay, high performance liquid chromatography, and western blot analysis were performed to assess the P-glycoprotein ATPase activity, the accumulation of NaF and rhodamine 123, and P-glycoprotein and MRP1 expression. The results showed that Z-guggulsterone (0-100 μM) significantly enhanced basal P-glycoprotein ATPase activity in a concentration-dependent manner. Tetrandrine (0.1, 0.3, 1 μM) or cyclosporine A (0.1, 0.3, 1 μM) had non-competitively inhibitory manner on Z-guggulsterone-stimulated P-glycoprotein ATPase activity, suggesting that Z-guggulsterone might have unique binding site or regulating site on P-glycoprotein. However, Z-guggulsterone (30, 100 μM) had almost no influence on MRP1 expression in rBMECs. Further results revealed that Z-guggulsterone (50mg/kg) significantly increased the accumulation of rhodamine 123 by down-regulating P-glycoprotein expression in rat brain, as compared with control (P<0.05). Our studies suggested that Z-guggulsterone potentially inhibited the activity and expression of P-glycoprotein in rBMECs and in rat brain.
authors.affiliation: Department of Pharmacy, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China; Department of Scientific Research, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China. Electronic address: xuhongbin@tongji.edu.cn.
authors.forename: Hong-Bin
authors.initials: HB
authors.lastname: Xu
authors.affiliation: Department of Pharmacy, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China; Department of Scientific Research, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China. Electronic address: dryujing@alyun.com.
authors.forename: Jing
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Pharmacy, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China; Department of Scientific Research, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
authors.forename: Lu-Zhong
authors.initials: LZ
authors.lastname: Xu
authors.affiliation: Department of Pharmacy, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China; Department of Scientific Research, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Fu
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism*; D002478:Cells, Cultured; D029744:Commiphora; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D010840:Phytosterols / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology; D011282:Pregnenediones / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D010840:Phytosterols; D011282:Pregnenediones; C023617:pregna-4,17-diene-3,16-dione
keywords: Multidrug resistance-associated protein 1; P-glycoprotein ATPase; Rhodamine 123; Z-guggulsterone