The two enantiomers of tetrahydropalmatine are inhibitors of P-gp, but not inhibitors of MRP1 or BCRP

Xenobiotica. 2012 Dec;42(12):1197-205. doi: 10.3109/00498254.2012.702247. Epub 2012 Aug 19.


Tetrahydropalmatine (THP), with one chiral centre, is one of the major constituents of Rhizoma corydalis. THP is considered to possess analgesic, sedative, hypnotic actions and cardiac protection. The aim of this study was to elucidate the stereoselective interaction between THP and ABC transporters. The present study investigated three most important ABC transporters, including P-glycoprotein (P-gp), multidrug resistance protein 1 (MRP1) and breast cancer resistance protein (BCRP). The intracellular accumulation and bidirectional transport suggested THP enantiomers were inhibitors of P-gp, but not of MRP1 or BCRP. The IC(50) values of (-)-THP and (+)-THP on rhodamine 123 (P-gp substrate) efflux were 48.6 and 20.0 µM, respectively, which showed obvious stereoselective difference. In the bidirectional transport, THP enantiomers showed high passive permeability and the contribution of P-gp could not be testified. The western blot and real-time RT-PCR assays showed that THP enantiomers reduced the protein expression of P-gp, but did not affect its mRNA expression. In in vitro cytotoxicity test, THP enantiomers showed the potential of increasing the cytotoxicity of doxorubicin in P-gp-mediated multidrug resistant tumour cells. The present study showed the stereoselective interaction between THP enantiomers and P-gp, which should be considered in clinical practice.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors*
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • ATP-Binding Cassette Transporters / antagonists & inhibitors
  • ATP-Binding Cassette Transporters / metabolism*
  • Animals
  • Berberine Alkaloids / chemistry*
  • Berberine Alkaloids / pharmacology*
  • Biological Transport / drug effects
  • Dogs
  • Drug Resistance, Multiple / drug effects
  • Fluoresceins / metabolism
  • Fluorobenzenes / metabolism
  • Gene Expression Regulation / drug effects
  • Humans
  • Intracellular Space / drug effects
  • Intracellular Space / metabolism
  • K562 Cells
  • LLC-PK1 Cells
  • MCF-7 Cells
  • Madin Darby Canine Kidney Cells
  • Multidrug Resistance-Associated Proteins / antagonists & inhibitors
  • Multidrug Resistance-Associated Proteins / metabolism*
  • Pyrimidines / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rhodamine 123 / metabolism
  • Rosuvastatin Calcium
  • Stereoisomerism
  • Sulfonamides / metabolism
  • Swine


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • ATP-Binding Cassette Transporters
  • Berberine Alkaloids
  • Fluoresceins
  • Fluorobenzenes
  • Multidrug Resistance-Associated Proteins
  • Pyrimidines
  • RNA, Messenger
  • Sulfonamides
  • calcein AM
  • Rhodamine 123
  • tetrahydropalmatine
  • Rosuvastatin Calcium
  • multidrug resistance-associated protein 1