The interaction between human breast cancer resistance protein (BCRP) and five bisbenzylisoquinoline alkaloids

Int J Pharm. 2013 Sep 10;453(2):371-9. doi: 10.1016/j.ijpharm.2013.05.053. Epub 2013 Jun 3.


BCRP is one of the key factors to drug absorption, distribution and elimination. Bisbenzylisoquinoline alkaloids are a large family of natural phytochemicals with great potential for clinical use. In this study, the interaction between BCRP and five bisbenzylisoquinoline alkaloids (neferine, isoliensinine, liensinine, dauricine and tetrandrine) were evaluated using LLC-PK1/BCRP cell model. The intracellular accumulation and bi-directional transport studies were conducted, and then molecular docking analysis was carried out employing a homology model of BCRP. Our study revealed that the permeability of these five alkaloids was not high, the Papp values were all less than 6.5 × 10(-6)cm/s. Liensinine and dauricine were substrates of BCRP: at lower concentration (10 μM), the net efflux ratios were 2.87 and 1.64 respectively. And their cellular accumulation was lower in LLC-PK1/BCRP cells than in LLC-PK1 cells. On the other hand, tetrandrine, isoliensinine and neferine were not substrates of BCRP. On the basis of docking studies, a direct hydrogen bond was formed between liensinine and arginine 482 which is a hot spot of BCRP for substrate specificity; and dauricine had hydrophobic interaction with BCRP. In conclusion, our study indicated that BCRP could mediate the excretion of liensinine and dauricine, thus influence their pharmacological activity and disposition.

Keywords: Bi-directional transport; Bisbenzylisoquinoline alkaloid; Cellular accumulation; Docking analysis; LLC-PK1/BCRP; Substrate.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters / genetics
  • ATP-Binding Cassette Transporters / metabolism*
  • Animals
  • Benzylisoquinolines / pharmacology*
  • Cell Membrane Permeability
  • Cell Survival / drug effects
  • Humans
  • LLC-PK1 Cells
  • Molecular Docking Simulation
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Swine


  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters
  • Benzylisoquinolines
  • Neoplasm Proteins