Functional consequences of single nucleotide polymorphisms in the human organic anion transporter hOAT1 (SLC22A6).
The human organic anion transporter hOAT1 (SLC22A6) contributes to the uptake of a range of small organic anions across the basolateral membrane of the renal proximal tubule and drives their urinary elimination. The aim of this study was to identify genetic variants of hOAT1 and to investigate potential effects on the functional properties of this transporter. Twenty single nucleotide polymorphisms (SNPs) in hOAT1 were identified in genomic DNA from 92 individuals of African, Asian, and Caucasian origin. Two SNPs encoded changes in amino acid sequence; arginine to histidine (residue 50) and lysine to isoleucine (residue 525). Significantly, these SNPs were only present in the samples of African origin. When expressed in Xenopus oocytes, wild-type R50-hOAT1 and the variants R50H-hOAT1 and K525I-hOAT1 all mediated the probenecid-sensitive uptake of the classic organic anion para-aminohippurate (PAH). Kinetic analysis indicated that the transport affinity (K(m)) for PAH was unchanged in the variants, compared with wild type. Interestingly, the K(m) for the nucleoside phosphonate analogs adefovir, cidofovir, and tenofovir seemed to be decreased in the R50H-hOAT1 variant compared with the wild type, whereas the kinetics of K525I-hOAT1 remained unchanged. In conclusion, this is the first study to identify variation of hOAT1 in a racially diverse sample and to investigate the functional properties of the resulting variants. Since hOAT1 has been suggested as the basis of nephrotoxicity induced by nucleoside phosphonate analogs, this study raises the intriguing possibility that individuals with genetic variation in hOAT1, such as R50H, may display different handling of these drugs.
Bleasby
Kelly
K
Laboratory of Pharmacology and Chemistry, The National Institute of Environmental Health Sciences, 111 T. W. Alexander Drive, Research Triangle Park, NC 27709, USA.
Hall
Laura A
LA
Perry
Jennifer L
JL
Mohrenweiser
Harvey W
HW
Pritchard
John B
JB
D000225:Adenine / Q000031:analogs & derivatives / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism; D000077404:Cidofovir; D003596:Cytosine / Q000031:analogs & derivatives / Q000378:metabolism; D004247:DNA / Q000235:genetics; D014644:Genetic Variation; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed / Q000235:genetics; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D027362:Organic Anion Transport Protein 1 / Q000235:genetics* / Q000378:metabolism*; D063065:Organophosphonates / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000502:physiology*; D018075:RNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000068698:Tenofovir; D014982:Xenopus laevis; D010130:p-Aminohippuric Acid / Q000378:metabolism
D000998:Antiviral Agents; D027362:Organic Anion Transport Protein 1; D063065:Organophosphonates; D018075:RNA, Complementary; D011994:Recombinant Proteins; C053001:adefovir; D003596:Cytosine; D004247:DNA; D000068698:Tenofovir; D000225:Adenine; D000077404:Cidofovir; D010130:p-Aminohippuric Acid