title: The functional influences of common ABCB1 genetic variants on the inhibition of P-glycoprotein by Antrodia cinnamomea extracts.
abstract: Antrodia cinnamomea is a traditional healthy food that has been demonstrated to possess anti-inflammatory, antioxidative, and anticacer effects. The purpose of this study was to evaluate whether the ethanolic extract of A. cinnamomea (EEAC) can affect the efflux function of P-glycoprotein (P-gp) and the effect of ABCB1 genetic variants on the interaction between EEAC and P-gp. To investigate the mechanism of this interaction, Flp-In™-293 cells stably transfected with various genotypes of human P-gp were established and the expression of P-gp was confirmed by Western blot. The results of the rhodamine 123 efflux assay demonstrated that EEAC efficiently inhibited wild-type P-gp function at an IC50 concentration of 1.51 ± 0.08 µg/mL through non-competitive inhibition. The IC50 concentrations for variant-type 1236T-2677T-3435T P-gp and variant-type 1236T-2677A-3435T P-gp were 5.56 ± 0.49 µg/mL and 3.33±0.67 µg/mL, respectively. In addition, the inhibition kinetics of EEAC also changed to uncompetitive inhibition in variant-type 1236T-2677A-3435T P-gp. The ATPase assay revealed that EEAC was an ATPase stimulator and was capable of reducing verapamil-induced ATPase levels. These results indicate that EEAC may be a potent P-gp inhibitor and higher dosages may be required in subjects carrying variant-types P-gp. Further studies are required to translate this basic knowledge into clinical applications.
authors.affiliation: Department of Pharmacy, College of Pharmacy, China Medical University, Taichung, Taiwan.
authors.forename: Ming-Jyh
authors.initials: MJ
authors.lastname: Sheu
authors.affiliation: Department of Pharmacy, College of Pharmacy, China Medical University, Taichung, Taiwan.
authors.forename: Yu-Ning
authors.initials: YN
authors.lastname: Teng
authors.affiliation: Department of Pharmacy, College of Pharmacy, China Medical University, Taichung, Taiwan.
authors.forename: Ying-Yi
authors.initials: YY
authors.lastname: Chen
authors.affiliation: Department of Pharmacy, College of Pharmacy, China Medical University, Taichung, Taiwan ; Department of Pharmacy, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Chin-Chuan
authors.initials: CC
authors.lastname: Hung
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors / Q000235:genetics; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000378:metabolism; D055491:Antrodia / Q000737:chemistry*; D014644:Genetic Variation; D057809:HEK293 Cells; D006801:Humans; D010936:Plant Extracts / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020112:Rhodamine 123 / Q000378:metabolism
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D010936:Plant Extracts; D012333:RNA, Messenger; D020112:Rhodamine 123; D000251:Adenosine Triphosphatases