title: Functional analysis of polymorphisms in the organic anion transporter, SLC22A6 (OAT1).
abstract: OBJECTIVE
  The organic anion transporter, OAT1 (SLC22A6), plays a role in the renal elimination of many drugs and environmental toxins. The goal of this study was to identify and functionally characterize OAT1 variants as a first step towards understanding whether genetic variation in OAT1 may contribute to interindividual differences in renal elimination of xenobiotics.
  
  
  METHODS
  As part of a larger study, 276 DNA samples from an ethnically diverse population were screened and 12 coding region variants of OAT1 were identified. The non-synonymous variants were then constructed and characterized in Xenopus laevis oocytes. A small family-based clinical study was conducted to determine the renal elimination of a model OAT1 substrate, adefovir (an antiviral agent) in human subjects who possessed a non-functional variant, OAT1-R454Q.
  
  
  RESULTS
  Six non-synonymous variants were identified; two (OAT1-R50 H and OAT1-R293W) were present at > or = 1% in at least one ethnic population. These two variants exhibited normal uptake of p-aminohippurate, ochratoxin A and methotrexate assayed in X. laevis oocytes. One variant, OAT1-R454Q, was non-functional with respect to the above substrates. In the clinical study, there was no significant decrease in the renal secretory clearance of adefovir in family members heterozygous for OAT1-454Q in comparison to those with the reference transporter, OAT1-454R.
  
  
  CONCLUSIONS
  These data indicate that the coding region of OAT1 has low genetic and functional diversity and suggest that coding region variants of OAT1 may not contribute substantially to interindividual differences in renal elimination of xenobiotics.
authors.affiliation: Department of Pharmacology, Kitasato University School of Medicine, Sagamihara, Kanagawa, 228-8555, Japan.
authors.forename: Tomoe
authors.initials: T
authors.lastname: Fujita
authors.forename: Chaline
authors.initials: C
authors.lastname: Brown
authors.forename: Elaine J
authors.initials: EJ
authors.lastname: Carlson
authors.forename: Travis
authors.initials: T
authors.lastname: Taylor
authors.forename: Melanie
authors.initials: M
authors.lastname: de la Cruz
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Johns
authors.forename: Doug
authors.initials: D
authors.lastname: Stryke
authors.forename: Michiko
authors.initials: M
authors.lastname: Kawamoto
authors.forename: Kazumi
authors.initials: K
authors.lastname: Fujita
authors.forename: Richard
authors.initials: R
authors.lastname: Castro
authors.forename: Chung-Wen
authors.initials: CW
authors.lastname: Chen
authors.forename: Emil T
authors.initials: ET
authors.lastname: Lin
authors.forename: Claire M
authors.initials: CM
authors.lastname: Brett
authors.forename: Esteban Gonzalez
authors.initials: EG
authors.lastname: Burchard
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Ferrin
authors.forename: Conrad C
authors.initials: CC
authors.lastname: Huang
authors.forename: Maya K
authors.initials: MK
authors.lastname: Leabman
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Giacomini
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000328:Adult; D000818:Animals; D000838:Anions / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology; D018076:DNA, Complementary / Q000378:metabolism; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D007668:Kidney / Q000378:metabolism; D007700:Kinetics; D008297:Male; D008727:Methotrexate / Q000494:pharmacology; D008956:Models, Chemical; D008957:Models, Genetic; D009183:Mycotoxins / Q000378:metabolism; D009793:Ochratoxins / Q000494:pharmacology; D027362:Organic Anion Transport Protein 1 / Q000235:genetics*; D027361:Organic Anion Transporters / Q000378:metabolism; D063065:Organophosphonates / Q000494:pharmacology; D010375:Pedigree; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D017433:Protein Structure, Secondary; D018075:RNA, Complementary / Q000378:metabolism; D015262:Xenobiotics / Q000494:pharmacology; D014982:Xenopus laevis; D010130:p-Aminohippuric Acid / Q000494:pharmacology
chemical_list: D000838:Anions; D000970:Antineoplastic Agents; D018076:DNA, Complementary; D009183:Mycotoxins; D009793:Ochratoxins; D027362:Organic Anion Transport Protein 1; D027361:Organic Anion Transporters; D063065:Organophosphonates; D018075:RNA, Complementary; D015262:Xenobiotics; C025589:ochratoxin A; C053001:adefovir; D000225:Adenine; D010130:p-Aminohippuric Acid; D008727:Methotrexate