title: Down-regulation of P-gp expression and function after Mulberroside A treatment: potential role of protein kinase C and NF-kappa B.
abstract: P-Glycoprotein (P-gp) plays a major role in drug-drug and herb-drug interactions. Mulberroside A (Mul A) is one of the main bioactive constituents of Sangbaipi, the dried root-bark of Morus alba L. (white mulberry), which is officially listed in the Chinese Pharmacopoeia. In the present study, we investigated the effect of Mul A treatment on mRNA expression and protein expression of P-gp in the Caco-2 cells by real-time qPCR and Western blot analysis. The effect of Mul A treatment on the function of P-gp in vitro and in vivo was assessed by Rho123 transport assay and a pharmacokinetic study. The potential roles of protein kinase C (PKC) and nuclear factor kappa B (NF-κB) in the expression regulation of P-gp after Mul A treatment were also investigated. The results revealed that Mul A treatment significantly decreased the mRNA and protein expression of P-gp in Caco-2 cells after treatment with Mul A (5-20 μM). Furthermore, Mul A treatment displayed apparently inhibitory effect on the function of P-gp both in vitro and in vivo. In addition, activation of PKC activity and NF-κB nuclear translocation were observed in the presence of Mul A, which suggested that PKC and NF-κB might play crucial roles in Mul A-induced suppression of P-gp. Our study demonstrated that Mul A treatment could down-regulate P-gp expression and function accompanied by the activation of PKC and NF-κB, and this should be taken into consideration in potential herb-drug interactions when Mul A or M. alba are co-administered with other drugs transported by P-gp.
authors: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong Province 510006, PR China.
authors: Yuhua
authors: Y
authors: Li
authors: School of Pharmaceutical Sciences, Hainan Medical University, Haikou, Hainan Province 571199, PR China.
authors: Ling
authors: L
authors: Huang
authors: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong Province 510006, PR China.
authors: Xuezhen
authors: X
authors: Zeng
authors: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong Province 510006, PR China.
authors: Guoping
authors: G
authors: Zhong
authors: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong Province 510006, PR China.
authors: Mengjia
authors: M
authors: Ying
authors: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong Province 510006, PR China. Electronic address: huangmin@mail.sysu.edu.cn.
authors: Min
authors: M
authors: Huang
authors: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong Province 510006, PR China. Electronic address: bihchang@mail.sysu.edu.cn.
authors: Huichang
authors: H
authors: Bi
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D018938:Caco-2 Cells; D004077:Digoxin / Q000097:blood / Q000493:pharmacokinetics; D004187:Disaccharides / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D020536:Enzyme Activators / Q000494:pharmacology; D006801:Humans; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism*; D011897:Random Allocation; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D013267:Stilbenes / Q000494:pharmacology*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004187:Disaccharides; D020536:Enzyme Activators; D016328:NF-kappa B; D013267:Stilbenes; C420606:mulberroside A; D004077:Digoxin; D011493:Protein Kinase C
keywords: Digoxin; Herb–drug interaction; Mulberroside A; Nuclear factor kappa B; P-Glycoprotein; Protein kinase C