The two enantiomers of tetrahydropalmatine are inhibitors of P-gp, but not inhibitors of MRP1 or BCRP.
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.
Department of Pharmaceutical Analysis and Drug Metabolism, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
Siyuan
S
Sun
Zhongjian
Z
Chen
Liping
L
Li
Dongli
D
Sun
Ye
Y
Tian
Hao
H
Pan
Huichang
H
Bi
Min
M
Huang
Su
S
Zeng
Huidi
H
Jiang
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D001600:Berberine Alkaloids / Q000737:chemistry* / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D004285:Dogs; D018432:Drug Resistance, Multiple / Q000187:drug effects; D005452:Fluoresceins / Q000378:metabolism; D005464:Fluorobenzenes / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D020014:K562 Cells; D018374:LLC-PK1 Cells; D061986:MCF-7 Cells; D061985:Madin Darby Canine Kidney Cells; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011743:Pyrimidines / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020112:Rhodamine 123 / Q000378:metabolism; D000068718:Rosuvastatin Calcium; D013237:Stereoisomerism; D013449:Sulfonamides / Q000378:metabolism; D013552:Swine
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D001600:Berberine Alkaloids; D005452:Fluoresceins; D005464:Fluorobenzenes; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011743:Pyrimidines; D012333:RNA, Messenger; D020112:Rhodamine 123; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides; C085925:calcein AM; C014215:tetrahydropalmatine; C421109:multidrug resistance-associated protein 1