Abstract
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 (Km) for PAH was unchanged in the variants, compared with wild type. Interestingly, the Km 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.
Footnotes
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This work was supported in part by The Wellcome Trust UK Grant GR061519MF. Work at Lawrence Livermore National Laboratory was performed under auspices of the U.S. Department of Energy by the University of California, contract no. W-7405-ENG-48, and supported in part by Interagency Agreement Y1-ES-8054-05 from National Institute of Environmental Health Sciences, National Institutes of Health. This work was presented previously, in part, in Drug Metabolism Rev (2002) 34 (Suppl 1):83.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.105.084301.
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ABBREVIATIONS: OAT, organic anion transporter; hOAT, human organic anion transporter, SNP, single nucleotide polymorphism; PAH, para-aminohippurate; PCR, polymerase chain reaction; ET, energy transfer; SIFT, sorting intolerant from tolerant; PSIC, position-specific independent counts.
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↵1 Current address: Department of Drug Metabolism, Merck Research Laboratories, Rahway, NJ 07065.
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↵2 Current address: Epidemiology Division, University of California, Irvine, Irvine, CA.
- Received January 31, 2005.
- Accepted May 19, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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