Role of P-glycoprotein in the transport of tanshinone I, one active triterpenoid from Salvia miltiorrhiza.
The extracts from the root of Salvia miltiorrhiza are widely used in the treatment of angina and stroke. In this study, we have investigated the role of P-glycoprotein (P-gp) in the transport of tanshinone I (TSI), a major active constituent of S. miltiorrhiza. The TSI transport across Caco-2 monolayers was pH-, energy-, and temperature-dependent, but not sodium-dependent. TSI exhibited a polarized transport in Caco-2 monolayers which was attenuated by P-gp inhibitors. The permeability (P(app)) values of TSI in the basolateral to apical direction were significantly higher in MDCK-II cells over-expressing MDR1, as compared to the wild-type control cells. Furthermore, TSI significantly inhibited the transport of digoxin in Caco-2 cells with an IC(50) value of 0.53 +/- 0.09 microM. TSI also moderately stimulated P-gp ATPase activity with K(m) and V(max) values of 31.70 +/- 7.09 microM and 57.71 +/- 5.26 nmol/min/mg protein, respectively. Our findings indicate that TSI is a substrate and inhibitor of P-gp, which has important clinical and toxicological implications.
Research Center of Medical Sciences, Guangdong Provincial People's Hospital, Guangdong Provincial Cardiovascular Institute, Guangzhou 510080, China.
Xing-Xiao
XX
Li
Zhi-Wei
ZW
Zhou
Shu-Feng
SF
Zhou
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects / Q000378:metabolism*; D045784:Abietanes; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D018938:Caco-2 Cells; D002460:Cell Line; D004077:Digoxin / Q000493:pharmacokinetics; D004285:Dogs; D006801:Humans; D006863:Hydrogen-Ion Concentration; D020128:Inhibitory Concentration 50; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism*; D010616:Phenanthrenes / Q000008:administration & dosage / Q000302:isolation & purification / Q000493:pharmacokinetics*; D018517:Plant Roots; D027561:Salvia miltiorrhiza / Q000737:chemistry*; D013696:Temperature
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D045784:Abietanes; D000251:Adenosine Triphosphatases; D004077:Digoxin; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010616:Phenanthrenes; C021751:tanshinone; C421109:multidrug resistance-associated protein 1