Analyses of 5′ regulatory region polymorphisms in human SLC22A6 (OAT1) and SLC22A8 (OAT3)

Abstract

Kidney excretion of numerous organic anionic drugs and endogenous metabolites is carried out by a family of multispecific organic anion transporters (OATs). Two closely related transporters, SLC22A6, initially identified by us as NKT and also known as OAT1, and SLC22A8, also known as OAT3 and ROCT, are thought to mediate the initial steps in the transport of organic anionic drugs between the blood and proximal tubule cells of the kidney. Coding region polymorphisms in these genes are infrequent and pairing of these genes in the genome suggests they may be coordinately regulated. Hence, 5¢ regulatory regions of these genes may be important factors in human variation in organic anionic drug handling. We have analyzed novel single nucleotide polymorphisms in the evolutionarily conserved 5¢ regulatory regions of the SLC22A6 and SLC22A8 genes (phylogenetic footprints) in an ethnically diverse sample of 96 individuals (192 haploid genomes). Only one polymorphism was found in the SLC22A6 5¢ regulatory region. In contrast, seven polymorphisms were found in the SLC22A8 5¢ regulatory region, two of which were common to all ethnic groups studied. Computational analysis permitted phase and haplotype reconstruction. Proximity of these non-coding polymorphisms to transcriptional regulatory elements (including potential sex steroid response elements) suggests a potential influence on the level of transcription of the SLC22A6 and/or SLC22A8 genes and will help define their role in variation in human drug, metabolite and toxin excretion. The clustering of OAT genes in the genome raises the possibility that nucleotide polymorphisms in SLC22A6 could also effect SLC22A8 expression, and vice versa.

Handling of Drugs, Metabolites, and Uremic Toxins by Kidney Proximal Tubule Drug Transporters

“…Early studies of transporter polymorphisms raised the possibility that multiple SNPs in basolateral (e.g., OAT1 and OAT3) (82,83) and apical (e.g., URAT1, OAT4, MRP2, and MRP4) drug transporters may affect the net transport of drugs, toxins, and metabolites from blood to urine (50,84). In addition, noncoding SNPs that regulate drug transporter expression might be particularly important (82,85).…”

“…In addition, noncoding SNPs that regulate drug transporter expression might be particularly important (82,85). These polymorphisms may explain differences in drug response and toxicity among individuals.…”

Current Updates in the Genetic Polymorphisms of Human Organic Anion Transporters (OATs)

“…In the untranslated and intronic regions of SLC22A6, a total of five SNPs were identified by Iida et al [54] from a cohort of 48 Japanese. Furthermore, one SNP (-3,655G>A) was also spotted in the evolutionarily conserved 5' regulatory region of SLC22A6 [55]. This polymorphism was present in a Pacific Islander descent, and accounted for 0.5% in the sample population [55].…”

“…Furthermore, one SNP (-3,655G>A) was also spotted in the evolutionarily conserved 5' regulatory region of SLC22A6 [55]. This polymorphism was present in a Pacific Islander descent, and accounted for 0.5% in the sample population [55].…”

“…Eight intronic and four 5'UTR SNPs were also reported in the same study. In addition, the study of Bhatnagar et al [55] reported seven novel SNPs in the 5 ' UTR of SLC22A8 gene, from 96 ethnically varied human probes Among them, two were with relatively high allele frequency (-1882G>C, 47%; -1851G>A, 20%), whilst the remaining had the allele frequency of 5% in the total population (n=192). These mutants were further investigated in terms of their functional consequence, since they are relatively common.…”