title: Transcellular transport of aconitine across human intestinal Caco-2 cells.
abstract: Aconitine (AC) is a highly toxic compound present in plants of the genus Aconitum. The transcellular transport mechanism of AC was investigated using Caco-2 cells. The flux of AC was time- and concentration-dependent in both apical-to-basolateral and the reverse direction. The efflux of AC was more than two-fold that in the opposite direction. The influx of AC was temperature-, pH- and Na(+)-dependent. Glucose markedly decreased the absorption of AC. However, the efflux of AC was temperature- and pH-dependent, but Na(+)-independent. Cyclosporin A and verapamil, both inhibitors of P-glycoprotein (P-gp), significantly decreased the efflux of AC. In addition, MK-571, an inhibitor of multidrug resistance-associated protein 2 (MRP2), exhibited the same trend but to a lesser extent. These results indicate that both the influx and efflux of AC across Caco-2 monolayers were through an active process. A pH-dependent carrier-mediated transport system was the major absorption mechanism and a sodium-dependent glucose transporter may be involved. The active efflux of AC across Caco-2 cells was mediated mainly by ABC-transporter P-gp. It is involved in reducing the toxicity of AC to organisms and is the major reasons for the poor absorption of AC in vivo.
authors.affiliation: Key Laboratory of Drug Metabolism and Pharmacokinetics, Beijing Institute of Pharmacology and Toxicology, No. 27 Taiping Road, Beijing 100850, China. yangsophia76@hotmail.com
authors.forename: Cuiping
authors.initials: C
authors.lastname: Yang
authors.forename: Zheng
authors.initials: Z
authors.lastname: Li
authors.forename: Tianhong
authors.initials: T
authors.lastname: Zhang
authors.forename: Fei
authors.initials: F
authors.lastname: Liu
authors.forename: Jinxiu
authors.initials: J
authors.lastname: Ruan
authors.forename: Zhenqing
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000157:Aconitine / Q000378:metabolism / Q000493:pharmacokinetics*; D018938:Caco-2 Cells / Q000187:drug effects* / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007408:Intestinal Absorption / Q000187:drug effects; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors; D011422:Propionates / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D012964:Sodium / Q000378:metabolism; D013696:Temperature; D057900:Transcytosis; D014700:Verapamil / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000157:Aconitine; D016572:Cyclosporine; D005947:Glucose; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011422:Propionates; D011804:Quinolines; D012964:Sodium; D014700:Verapamil; C000715087:ABCC2 protein, human; C059141:verlukast