Effects of various principles from Chinese herbal medicine on rhodamine123 accumulation in brain capillary endothelial cells.
OBJECTIVE
To search for novel effective P-glycoprotein (P-gp) reversal agents in the blood-brain barrier (BBB).


METHODS
Using rhodamine123 (Rh123) to examine the functional activity of P-gp in cultured bovine brain capillary endothelial cells (BCEC) and screen various principles on P-gp modulation in BBB.


RESULTS
All of tested compounds (1-10 micromol/L) increased the intracellular accumulation of Rh123 in a concentration-dependent manner. The rank order of these agents in increasing Rh123 accumulation in BCEC was: cyclosporin A (CsA) > tetrandrine (Tet) > vincrinstine (VCR) approximate, equals flunarizine (Flu) > dl-tetrahydropalmatine (dl-THP) > dauricine (DRC) > azithromycin (Azi) > verapamil (Ver) approximate, equals berbamine (BBM) > daurisoline (DRS) > berberine (BBR) approximate, equals doxorubicin (Dox) > l-tetrahydropalmatine (l-THP) > tetramethylpyrazine (TMP). These agents at concentration of 10 micromol/L increased Rh123 accumulation by 346 %, 203 %, 136 %, 129 %, 115 %, 103 %, 92 %, 87 %, 81 %, 75 %, 67 %, 67 %, 63 %, and 54 %, respectively. The effects of CsA, Tet, Ver, Flu, Azi, and dl-THP on cellular accumulation of Rh123 in BCEC were reversible. When CsA, Tet, Ver, Flu, Azi, or dl-THP-pretreated BCEC were examined at 48, 36, 24, 36, 36, or 12 h, respectively, after removing the agent, the amount of cellular Rh123 accumulation in BCEC returned to control levels (no drug treatment).


CONCLUSIONS
The functional activity of P-gp on the blood-brain barrier could be modulated by various MDR-reversing agents and some principles with low toxicity extracted from medicinal herbs, such as some isoquinoline alkaloids without permanent modifying effects on the intrinsic level of P-gp function.
He
Ling
L
Department of Pharmacology, China Pharmaceutical University, Nanjing 210009, China. hexyz@263.net
Liu
Guo-Qing
GQ
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000470:Alkaloids / Q000302:isolation & purification / Q000494:pharmacology; D000818:Animals; D044182:Benzylisoquinolines / Q000302:isolation & purification / Q000494:pharmacology; D001812:Blood-Brain Barrier; D001921:Brain / Q000098:blood supply*; D002196:Capillaries / Q000166:cytology; D002417:Cattle; D002478:Cells, Cultured; D018432:Drug Resistance, Multiple; D004365:Drugs, Chinese Herbal / Q000302:isolation & purification / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D005456:Fluorescent Dyes; D010946:Plants, Medicinal / Q000737:chemistry; D020112:Rhodamine 123 / Q000378:metabolism*; D044005:Tetrahydroisoquinolines / Q000302:isolation & purification / Q000494:pharmacology; D014750:Vincristine / Q000302:isolation & purification / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000470:Alkaloids; D044182:Benzylisoquinolines; D004365:Drugs, Chinese Herbal; D005456:Fluorescent Dyes; D044005:Tetrahydroisoquinolines; D020112:Rhodamine 123; C009438:tetrandrine; D014750:Vincristine; C035934:dauricine