title: Impact of genetic variability in the ABCG2 gene on ABCG2 expression, function, and interaction with AT1 receptor antagonist telmisartan.
abstract: The ATP-binding cassette transporter ABCG2 plays a prominent role in cardiovascular and cancer pathophysiology, is involved in the pathogenesis of gout, and affects pharmacokinetics of numerous drugs. Telmisartan, a widely used AT1 receptor antagonist, inhibits the transport capacity of ABCG2 and may cause drug-drug interactions, especially in individuals carrying polymorphism that facilitate the telmisartan-ABCG2 interaction. Thus, the aim of this study was to identify ABCG2 polymorphisms and somatic mutations with relevance for the telmisartan-ABCG2 interaction. For this purpose, a cellular system for the conditional expression of ABCG2 was established. ABCG2 variants were generated via site-directed mutagenesis. Interaction of telmisartan with these ABCG2 variants was investigated in HEK293-Tet-On cells using the pheophorbide A efflux assay. Moreover, expression of ABCG2 variants was studied in these cells. Importantly, protein levels of the Q141K and F489L variant were significantly reduced, a phenomenon that was partly reversed by pharmacological proteasome inhibition. Moreover, basal pheophorbide A efflux capacity of S248P, F431L, and F489L variants was significantly impaired. Interestingly, inhibition of ABCG2-mediated pheophorbide A transport by telmisartan was almost abolished in cells expressing the R482G variant, whereas it was largely increased in cells expressing the F489L variant. We conclude that the arginine residue at position 482 of the ABCG2 molecule is of major importance for the interaction of telmisartan with this ABC transporter. Furthermore, individuals carrying the F489L polymorphism may be at increased risk of developing adverse drug reactions in multi-drug regimens involving ABCG2 substrates and telmisartan.
authors.affiliation: Technical University of Braunschweig, Institute of Pharmacology, Toxicology, and Clinical Pharmacy, Braunschweig, Germany.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Deppe
authors.affiliation: Martin-Luther-University Halle-Wittenberg, Department of Clinical Pharmacy and Pharmacotherapy, Halle (Saale), Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Ripperger
authors.affiliation: Department of Clinical Pharmacology and Pharmacoepidemiology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Johanna
authors.initials: J
authors.lastname: Weiss
authors.affiliation: Julius-Maximilians-Universität Würzburg, Institute of Anatomy and Cell Biology, Würzburg, Germany.
authors.forename: Süleyman
authors.initials: S
authors.lastname: Ergün
authors.affiliation: Martin-Luther-University Halle-Wittenberg, Department of Clinical Pharmacy and Pharmacotherapy, Halle (Saale), Germany. Electronic address: ralf.benndorf@pharmazie.uni-halle.de.
authors.forename: Ralf A
authors.initials: RA
authors.lastname: Benndorf
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001120:Arginine / Q000737:chemistry; D001562:Benzimidazoles / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001565:Benzoates / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001665:Binding Sites / Q000235:genetics; D002734:Chlorophyll / Q000031:analogs & derivatives / Q000378:metabolism; D014644:Genetic Variation; D057809:HEK293 Cells; D006801:Humans; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D011110:Polymorphism, Genetic; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000077333:Telmisartan
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001565:Benzoates; D009363:Neoplasm Proteins; D011994:Recombinant Proteins; D002734:Chlorophyll; D001120:Arginine; C032623:pheophorbide a; D000077333:Telmisartan
keywords: ABCG2; AT1 receptor antagonists; ATP-binding cassette (ABC) transporter; Polymorphism; Telmisartan