Functional analysis of polymorphisms in the organic anion transporter, SLC22A6 (OAT1).
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.
Fujita
Tomoe
T
Department of Pharmacology, Kitasato University School of Medicine, Sagamihara, Kanagawa, 228-8555, Japan.
Brown
Chaline
C
Carlson
Elaine J
EJ
Taylor
Travis
T
de la Cruz
Melanie
M
Johns
Susan J
SJ
Stryke
Doug
D
Kawamoto
Michiko
M
Fujita
Kazumi
K
Castro
Richard
R
Chen
Chung-Wen
CW
Lin
Emil T
ET
Brett
Claire M
CM
Burchard
Esteban Gonzalez
EG
Ferrin
Thomas E
TE
Huang
Conrad C
CC
Leabman
Maya K
MK
Giacomini
Kathleen M
KM
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
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