title: Different transport activity of human triallelic MDR1 893Ala/Ser/Thr variant and its association with herb extracts.
abstract: Individual pharmacokinetic differences for herb-drug interaction have been associated with genetic variations of the multidrug resistance (MDR) gene. A high level expression of MDR protein increases cellular efflux and might decrease drug sensitivity. This study investigated the drug efflux activity difference of human MDR1 triallelic variant 2677G/T/A (rs2032582), as a nonsynonymous 893Ala/Ser/Thr, using Xenopus laevis oocytes and MDR1 overexpressing LLC-PK1 cells. Two MDR1 variants (2667T/893Ser and 2667A/893Thr) were generated using human MDR1 cDNA (2677G/893Ala). No significant difference in the expression of MDR1 893Ala/Ser/Thr was found in X. laevis oocytes. However, the MDR1 2667A/893Thr variant interestingly showed a significant decrease of efflux activity for both digoxin and daunorubicin compared with those of 893Ala and 893Ser variants. In further investigation assessing the inhibitory effects of three herbal extracts on MDR1, 893Ala and 893Ser showed significant decreases of efflux activities in treatments with P. cocos (p = 0.005 for 893Ser) and D. dasycarpus (p = 0.0009 for 893Ala; p = 0.002 for 893Ser) in X. laevis oocytes. The results in this study suggest that herbal medicines could interact with other drugs and change the therapeutic effects depending on the genetic polymorphisms of individuals.
authors.affiliation: Department of Preventive Medicine, College of Oriental Medicine, Kyung Hee University, Seoul, Republic of Korea.
authors.forename: Jeong-Hyun
authors.initials: JH
authors.lastname: Kim
authors.forename: Soon Re
authors.initials: SR
authors.lastname: Kim
authors.forename: Im-Sook
authors.initials: IS
authors.lastname: Song
authors.forename: Ho-Jung
authors.initials: HJ
authors.lastname: Shin
authors.forename: Han-Seop
authors.initials: HS
authors.lastname: Kim
authors.forename: Jung-Ha
authors.initials: JH
authors.lastname: Lee
authors.forename: Seong-Gyu
authors.initials: SG
authors.lastname: Ko
authors.forename: Yong-Cheol
authors.initials: YC
authors.lastname: Shin
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D003630:Daunorubicin / Q000493:pharmacokinetics; D036905:Dictamnus / Q000737:chemistry; D004077:Digoxin / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics; D019450:Genes, MDR / Q000187:drug effects; D014644:Genetic Variation; D041743:Herb-Drug Interactions; D006801:Humans; D018374:LLC-PK1 Cells; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D010936:Plant Extracts / Q000493:pharmacokinetics / Q000494:pharmacology*; D055441:Poria / Q000737:chemistry; D029045:Rhus / Q000737:chemistry; D013552:Swine; D014982:Xenopus laevis
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D010936:Plant Extracts; D004077:Digoxin; D003630:Daunorubicin