BACKGROUND: Excretion by the kidney of a variety of organic anionic drugs and metabolites is mediated by a family of multispecific organic anion transporters (OAT genes) that are part of the SLC22 family of solute carriers. Different OATs localize to the apical (OAT2, OAT4, and RST/URAT) or basolateral (OAT1/NKT and OAT3) membranes of the renal proximal tubule; the net transport of organic anions from blood to urine is believed to require both apical and basolateral OATs. These genes are also thought to mediate transport of organic anionic drugs and metabolites (e.g., urate) across choroid plexus, retina, placenta, and possibly olfactory mucosa. The extent of functional redundancy among OATs remains uncertain, but closely related OAT genes are tightly linked in the genome. Hence, a better understanding of human variation in organic anionic drug excretion may be obtained by studying OAT genes in combination rather than individually. METHODS: We have analyzed single nucleotide polymorphisms (SNPs) in OAT1 (NKT), OAT2, OAT3, OAT4, and URAT1 (human homologue of RST) in an ethnically diverse sample of 96 individuals (192 haploid genomes). Ka/Ks analysis was also performed as well as haplotype reconstruction using the software program Arelquin. RESULTS: The data indicate that (1) nonsynonymous SNPs in OAT1 and OAT3 may not be frequent so it will be important to consider promoter region SNPs that regulate gene expression; (2) certain ethnic groups may have a high prevalence of nonsynonymous SNPs in particular OATs (e.g., OAT4 in Sub-Saharan Africans); (3) there are individuals who have nonsynonymous SNPs in apical and basolateral OATs; (4) nonsynonymous OAT4 SNPs may be more frequent, raising the possibility of altered maternofetal transport of drugs and metabolites; and (5) combinations of synonymous SNPs in OAT1 and OAT3 also occur in certain individuals. In addition, Ka/Ks analysis of human, chimp and rodent genes suggests that OAT4 is under accelerated selection pressure, perhaps reflecting specific human environmental exposures during evolution. In contrast, Ka/Ks analysis for URAT1 suggests decelerated selection pressure. Haplotype reconstruction also supports this view. CONCLUSION: Together, these data suggest that, in order to understand the effect of SNPs in genes of the SLC22 family on drug handling as well as excretion of metabolites like uric acid, it is important to consider the entire set of organic anion transporters. It will be particularly interesting to determine if individuals with nonsynonymous apical and basolateral SNPs have altered handling (and toxicity) of organic anionic drugs and metabolites. Certain OAT family members appear to be under greater evolutionary selection pressure.
BACKGROUND: Excretion by the kidney of a variety of organic anionic drugs and metabolites is mediated by a family of multispecific organic anion transporters (OAT genes) that are part of the SLC22 family of solute carriers. Different OATs localize to the apical (OAT2, OAT4, and RST/URAT) or basolateral (OAT1/NKT and OAT3) membranes of the renal proximal tubule; the net transport of organic anions from blood to urine is believed to require both apical and basolateral OATs. These genes are also thought to mediate transport of organic anionic drugs and metabolites (e.g., urate) across choroid plexus, retina, placenta, and possibly olfactory mucosa. The extent of functional redundancy among OATs remains uncertain, but closely related OAT genes are tightly linked in the genome. Hence, a better understanding of human variation in organic anionic drug excretion may be obtained by studying OAT genes in combination rather than individually. METHODS: We have analyzed single nucleotide polymorphisms (SNPs) in OAT1 (NKT), OAT2, OAT3, OAT4, and URAT1 (human homologue of RST) in an ethnically diverse sample of 96 individuals (192 haploid genomes). Ka/Ks analysis was also performed as well as haplotype reconstruction using the software program Arelquin. RESULTS: The data indicate that (1) nonsynonymous SNPs in OAT1 and OAT3 may not be frequent so it will be important to consider promoter region SNPs that regulate gene expression; (2) certain ethnic groups may have a high prevalence of nonsynonymous SNPs in particular OATs (e.g., OAT4 in Sub-Saharan Africans); (3) there are individuals who have nonsynonymous SNPs in apical and basolateral OATs; (4) nonsynonymous OAT4 SNPs may be more frequent, raising the possibility of altered maternofetal transport of drugs and metabolites; and (5) combinations of synonymous SNPs in OAT1 and OAT3 also occur in certain individuals. In addition, Ka/Ks analysis of human, chimp and rodent genes suggests that OAT4 is under accelerated selection pressure, perhaps reflecting specific human environmental exposures during evolution. In contrast, Ka/Ks analysis for URAT1 suggests decelerated selection pressure. Haplotype reconstruction also supports this view. CONCLUSION: Together, these data suggest that, in order to understand the effect of SNPs in genes of the SLC22 family on drug handling as well as excretion of metabolites like uric acid, it is important to consider the entire set of organic anion transporters. It will be particularly interesting to determine if individuals with nonsynonymous apical and basolateral SNPs have altered handling (and toxicity) of organic anionic drugs and metabolites. Certain OAT family members appear to be under greater evolutionary selection pressure.
Authors: Lucy Sanchez-Covarrubias; Lauren M Slosky; Brandon J Thompson; Thomas P Davis; Patrick T Ronaldson Journal: Curr Pharm Des Date: 2014 Impact factor: 3.116