Inhibitory effects of neochamaejasmin B on P-glycoprotein in MDCK-hMDR1 cells and molecular docking of NCB binding in P-glycoprotein

Stellera chamaejasme L. (Thymelaeaceae) is widely distributed in Mongolia, Tibet and the northern parts of China. Its roots are commonly used as "Langdu", which is embodied in the Pharmacopoeia of the P.R. China (2010) as a toxic Traditional Chinese Medicine. It is claimed to have antiviru...

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Published in:	Molecules (Basel, Switzerland) Switzerland), 2015-02, Vol.20 (2), p.2931-2948
Main Authors:	Pan, Lanying, Hu, Haihong, Wang, Xiangjun, Yu, Lushan, Jiang, Huidi, Chen, Jianzhong, Lou, Yan, Zeng, Su
Format:	Article
Language:	eng
Subjects:	Animals ATP Binding Cassette Transporter, Subfamily B - chemistry ATP Binding Cassette Transporter, Subfamily B - genetics ATP Binding Cassette Transporter, Subfamily B - metabolism biflavonoid Biflavonoids - chemistry Biflavonoids - isolation & purification Biflavonoids - pharmacology Cytotoxicity Dogs Glycoproteins inhibition Laboratories Madin Darby Canine Kidney Cells Medicine Metabolism Models, Molecular Molecular Docking Simulation molecular simulation Molecular Structure neochamaejasmin B P-gp Plant Proteins - chemistry Plant Proteins - isolation & purification Plant Proteins - pharmacology Protein Binding Protein Conformation suppression Thymelaeaceae - metabolism Toxicity
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Summary:	Stellera chamaejasme L. (Thymelaeaceae) is widely distributed in Mongolia, Tibet and the northern parts of China. Its roots are commonly used as "Langdu", which is embodied in the Pharmacopoeia of the P.R. China (2010) as a toxic Traditional Chinese Medicine. It is claimed to have antivirus, antitumor and antibacterial properties in China and other Asian countries. Studies were carried out to characterize the inhibition of neochamaejasmin B (NCB) on P-glycoprotein (P-gp, ABCB1, MDR1). Rhodamine-123 (R-123) transport and accumulation studies were performed in MDCK-hMDR1 cells. ABCB1 (MDR1) mRNA gene expression and P-gp protein expression were analyzed. Binding selectivity studies based on molecular docking were explored. R-123 transport and accumulation studies in MDCK-hMDR1 cells indicated that NCB inhibited the P-gp-mediated efflux in a concentration-dependent manner. RT-PCR and Western blot demonstrated that the P-gp expression was suppressed by NCB. To investigate the inhibition type of NCB on P-gp, Ki and Ki' values were determined by double-reciprocal plots in R-123 accumulation studies. Since Ki was greater than Ki', the inhibition of NCB on P-gp was likely a mixed type of competitive and non-competitive inhibition. The results were confirmed by molecular docking in our current work. The docking data indicated that NCB had higher affinity to P-gp than to Lig1 ((S)-5,7-dihydroxy-2-(4-hydroxyphenyl)chroman-4-one).
ISSN:	1420-3049 1420-3049