title: The human organic anion transporter 3 (OAT3; SLC22A8): genetic variation and functional genomics.
abstract: The human organic anion transporter, OAT3 (SLC22A8), plays a critical role in renal drug elimination, by mediating the entry of a wide variety of organic anions, including a number of commonly used pharmaceuticals, into the renal proximal tubular cells. To understand the nature and extent of genetic variation in OAT3, and to determine whether such variation affects its function, we identified OAT3 variants in a large, ethnically diverse sample population and studied their transport activities in cellular assays. We identified a total of 10 distinct coding-region variants, which altered the encoded amino acid sequence, in DNA samples from 270 individuals (80 African-Americans, 80 European-Americans, 60 Asian-Americans, and 50 Mexican-Americans). The overall prevalence of these OAT3 variants was relatively low among the screened population, with only three variants having allele frequencies of >1% in a particular ethnic group. Clones of each variant were created by site-directed mutagenesis, expressed in HEK-293 cells, and tested for function using the model substrates, estrone sulfate (ES) and cimetidine (CIM). The results revealed a high degree of functional heterogeneity among OAT3 variants, with three variants (p. Arg149Ser, p. Gln239Stop, and p. Ile260Arg) that resulted in complete loss of function, and several others with significantly reduced function. One of the more common variants (p. Ile305Phe), found in 3.5% of Asian-Americans, appeared to have altered substrate specificity. This variant exhibited a reduced ability to transport ES, but a preserved ability to transport CIM. These data suggest that genetic variation in OAT3 may contribute to variation in the disposition of drugs.
authors.affiliation: Department of Biopharmaceutical Sciences, University of California, San Francisco 94143-0446, USA.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Erdman
authors.forename: Lara M
authors.initials: LM
authors.lastname: Mangravite
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Urban
authors.forename: Leah L
authors.initials: LL
authors.lastname: Lagpacan
authors.forename: Richard A
authors.initials: RA
authors.lastname: Castro
authors.forename: Melanie
authors.initials: M
authors.lastname: de la Cruz
authors.forename: Wendy
authors.initials: W
authors.lastname: Chan
authors.forename: Conrad C
authors.initials: CC
authors.lastname: Huang
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Johns
authors.forename: Michiko
authors.initials: M
authors.lastname: Kawamoto
authors.forename: Douglas
authors.initials: D
authors.lastname: Stryke
authors.forename: Travis R
authors.initials: TR
authors.lastname: Taylor
authors.forename: Elaine J
authors.initials: EJ
authors.lastname: Carlson
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Ferrin
authors.forename: Claire M
authors.initials: CM
authors.lastname: Brett
authors.forename: Esteban G
authors.initials: EG
authors.lastname: Burchard
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Giacomini
mesh_terms: D000483:Alleles; D004252:DNA Mutational Analysis; D005006:Ethnicity; D014644:Genetic Variation; D005828:Genetics, Population; D006801:Humans; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics* / Q000502:physiology*; D004364:Pharmaceutical Preparations / Q000378:metabolism; D010599:Pharmacokinetics
chemical_list: D029362:Organic Anion Transporters, Sodium-Independent; D004364:Pharmaceutical Preparations; C114338:organic anion transport protein 3