title: The role of efflux transporters on the transport of highly toxic aconitine, mesaconitine, hypaconitine, and their hydrolysates, as determined in cultured Caco-2 and transfected MDCKII cells.
abstract: Aconitum alkaloids including aconitine (AC), mesaconitine (MA), hypaconitine (HA), are highly toxic. Their hydrolysates, such as benzoylaconine (BAC), benzoylmesaconine (BMA), benzoylhypaconine (BHA), aconine, and mesaconine, are considerably less toxic. Efflux transporters, including P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug resistance-associated protein isoform 2 (MRP2), act as a first line of defence and play key roles in toxicity prevention. The aim of the present study was to determine the role of efflux transporters in the transport of Aconitum alkaloids using cultured Caco-2, MDR1-MDCKII and BCRP-MDCKII cells. Bidirectional transport assays of the Aconitum alkaloids were performed with or without P-gp (cyclosporine A and verapamil), BCRP (Ko143) and MRP2 (MK571) inhibitors. The efflux ratios (Er) of AC, MA, and HA in Caco-2 cells were 34.6±4.2, 29.7±2.1, and 15.6±2.1, respectively; those of BAC, BMA, and BHA were approximately 4, and those of aconine and mesaconine were equal to 1. The Er values of AC, MA, and HA in MDR1-MDCKII and BCRP-MDCKII cells were significantly higher than those in parental MDCKII cells. Taken together the results of Er values and intracellular amounts in the presence of inhibitors, P-gp and BCRP were involved in the transport of AC, MA and HA; and MRP2 might transport AC, MA, HA, BAC, BMA and BHA.
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Ye
authors.forename: Xiaoshan
authors.initials: X
authors.lastname: Yang
authors.forename: Zhen
authors.initials: Z
authors.lastname: Yang
authors.forename: Song
authors.initials: S
authors.lastname: Gao
authors.forename: Taijun
authors.initials: T
authors.lastname: Yin
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.forename: Ming
authors.initials: M
authors.lastname: Hu
authors.forename: Zhongqiu
authors.initials: Z
authors.lastname: Liu
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000157:Aconitine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000633:toxicity; D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport; D018938:Caco-2 Cells; D016572:Cyclosporine / Q000494:pharmacology; D054659:Diketopiperazines; D004285:Dogs; D006576:Heterocyclic Compounds, 4 or More Rings; D006801:Humans; D007408:Intestinal Absorption; D061985:Madin Darby Canine Kidney Cells; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011422:Propionates / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D014162:Transfection; D014700:Verapamil / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000157:Aconitine; D000241:Adenosine; D016572:Cyclosporine; D054659:Diketopiperazines; D006576:Heterocyclic Compounds, 4 or More Rings; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D011422:Propionates; D011804:Quinolines; D014700:Verapamil; C541506:3-(6-isobutyl-9-methoxy-1,4-dioxo-1,2,3,4,6,7,12,12a-octahydropyrazino(1',2'-1,6)pyrido(3,4-b)indol-3-yl)propionic acid tert-butyl ester; C000715087:ABCC2 protein, human; C116614:ABCG2 protein, human; C058309:hypaconitine; C059141:verlukast; C019470:mesaconitine