title: Genetic variants in multidrug and toxic compound extrusion-1, hMATE1, alter transport function.
abstract: hMATE1 (human multidrug and toxin compound extrusion-1; encoded by SLC47A1) is thought to have an important function in the renal and hepatic elimination of drugs, endogenous compounds and environmental toxins. The goals of this study were to identify genetic variants of hMATE1 and to determine their effects on hMATE1 transport function. We identified four synonymous and six nonsynonymous, coding region variants in DNA samples from 272 individuals (68 Caucasians, 68 African Americans, 68 Asian Americans and 68 Mexican Americans). The overall prevalence of hMATE1 nonsynonymous variants was relatively low with three singleton variants and three variants having allele frequencies > or =2% in a specific ethnic group. The nonsynonymous hMATE1 variants were constructed and stably transfected into HEK-293 cells. Uptake studies using four known hMATE1 substrates (paraquat, metformin, tetraethylammonium and oxaliplatin) were performed in cells transfected with hMATE1 reference or variants. We found that two singleton variants, G64D and V480M, produced a complete loss of function for all four tested substrates whereas three polymorphic variants (allele frequencies > or =2%), L125F, V338I and C497S, significantly altered the transport function in a substrate-dependent manner. Confocal microscopy studies were consistent with functional studies suggesting that the altered function of the variants was due to altered localization to the plasma membrane. These data suggest that nonsynonymous variants in hMATE1 may alter drug disposition and ultimately affect clinical drug response.
authors.affiliation: Division of Clinical Pharmacology and Experimental Therapeutics, Department of Biopharmaceutical Sciences, University of California at San Francisco, San Francisco, CA 94158, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.forename: Kristen
authors.initials: K
authors.lastname: Teranishi
authors.forename: Shuanglian
authors.initials: S
authors.lastname: Li
authors.forename: Sook Wah
authors.initials: SW
authors.lastname: Yee
authors.forename: Stephanie
authors.initials: S
authors.lastname: Hesselson
authors.forename: Doug
authors.initials: D
authors.lastname: Stryke
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Johns
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Ferrin
authors.forename: Pui
authors.initials: P
authors.lastname: Kwok
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Giacomini
mesh_terms: D001741:Black or African American / Q000235:genetics; D001213:Asian / Q000235:genetics; D001692:Biological Transport / Q000235:genetics; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D005787:Gene Frequency; D005838:Genotype; D006630:Hispanic or Latino / Q000235:genetics; D006801:Humans; D007700:Kinetics; D008687:Metformin / Q000378:metabolism; D018613:Microscopy, Confocal; D027701:Organic Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000378:metabolism / Q000633:toxicity; D000077150:Oxaliplatin; D010269:Paraquat / Q000378:metabolism; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D019789:Tetraethylammonium / Q000378:metabolism; D014162:Transfection; D044465:White People / Q000235:genetics
chemical_list: D027701:Organic Cation Transport Proteins; D009944:Organoplatinum Compounds; C521869:SLC47A1 protein, human; D000077150:Oxaliplatin; D019789:Tetraethylammonium; D008687:Metformin; D010269:Paraquat