Disease relevance of SLC22A8

• In this study, the mRNA levels of the organic ion transporters were quantified by real-time PCR in normal parts of renal tissues from seven nephrectomized patients with renal cell carcinoma, and the distributions and localization of human (h)OAT1, hOAT3, and hOCT2 proteins were investigated by immunohistochemical analyses in the human kidney [1].
• CONCLUSIONS: These results suggest that the hOAT3 mRNA level is a significant marker of pharmacokinetics with which to predict the rate of elimination of cefazolin in patients with mesangial proliferative glomerulonephritis [2].

High impact information on SLC22A8

• Stable isomers of 1-SMP, (2-SMP and 4-SMP) competitively inhibited the uptake of characteristic substrates p-aminohippurate for hOAT1 and estrone sulfate for hOAT3 [3].
• Transactivation assays revealed that HNF1alpha and HNF1beta markedly increased hOAT3 promoter activity, where the transactivation potency of HNF1beta was lower than that of HNF1alpha [4].
• It was also demonstrated that the promoter activity of hOAT3 is repressed by DNA methylation [4].
• This suggests a synergistic action of the HNF1alpha/HNF1alpha homodimer or HNF1alpha/HNF1beta heterodimer and DNA demethylation for the constitutive expression of hOAT3 [4].
• The minimal promoter of hOAT3 was identified to be located approximately 300 base pairs upstream of the transcriptional start site, where there are canonical TATA and hepatocyte nuclear factor (HNF1) binding motifs, which are conserved in the rodent Oat3 genes [4].

Biological context of SLC22A8

• The human organic anion transporter 3 (OAT3; SLC22A8): genetic variation and functional genomics [5].
• METHODS: We analysed 22 polymorphisms in the OAT coding genes SLC22A6, SLC22A8 and SLC22A11 and their haplotypes and measured torsemide renal clearance in 95 healthy men [6].
• The clustering of OAT genes in the genome raises the possibility that nucleotide polymorphisms in SLC22A6 could also effect SLC22A8 expression, and vice versa [7].
• In contrast, seven polymorphisms were found in the SLC22A8 5' regulatory region, two of which were common to all ethnic groups studied [7].
• 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 [7].

Anatomical context of SLC22A8

• When human OAT3 (hOAT3) and hOAT4 were expressed in Xenopus laevis oocytes, only hOAT3 showed [3H]cortisol uptake in excess of that of water-injected control oocytes [8].
• Organic anion transporters, such as Oatp3 and Oat3, play a major role in the uptake of amphipathic and hydrophilic organic anions, respectively, at the brush border surface of the CPE, while the organic cation transporters, Oct2 and/or Oct3, have been suggested to be involved in the uptake of hydrophilic organic cations [9].
• Immunohistochemical analysis revealed that hOAT1 and hOAT3 are expressed in the cytoplasmic membrane and cytoplasm of human choroid plexus [10].
• In contrast, OAT3 abundance in both kidney cortex homogenates and in basolateral membranes increased by 3 days after the ligation [11].
• The purpose of the present study was to elucidate the expression of human organic anion transporter 1 (hOAT1) and hOAT3 in the choroid plexus of the human brain and their interactions with neurotransmitter metabolites using stable cell lines [10].

Associations of SLC22A8 with chemical compounds

• The uptake of DHEAS consists of two saturable components with K(m) values of 2.2 to 3.9 and 1300 muM, and the K(m) value of the high-affinity component was close to that for hOAT3 [12].
• These results suggest that the renal drug-drug interaction between fexofenadine and probenecid is probably explained by an inhibition of the renal uptake of fexofenadine via hOAT3, at least in part [13].
• Inhibition of oat3-mediated renal uptake as a mechanism for drug-drug interaction between fexofenadine and probenecid [13].
• RESULTS: The uptake of adefovir, cidofovir and tenofovir in monolayers stably expressing hOAT3 increased time-dependently, compared with control [14].
• Renal Transport of Adefovir, Cidofovir, and Tenofovir by SLC22A Family Members (hOAT1, hOAT3, and hOCT2) [14].

Physical interactions of SLC22A8

• Inhibition potency of probenecid for the uptake of fexofenadine was compared between hOAT3 and organic anion-transporting peptide 1B3 (hOATP1B3), a transporter responsible for the hepatic uptake of fexofenadine (Drug Metab Dispos 33:1477-1481, 2005) [13].
• The half-maximal inhibitory concentrations of famotidine for [3H]estrone sulfate transport by hOAT3 and [14C]tetraethylammonium transport by hOCT2 (300 microM and 1.8 mM, respectively) were higher than those of cimetidine (53 and 67 microM, respectively) [15].

Other interactions of SLC22A8

• RESULTS: Among 120 healthy individuals, 5 nonsynonymous variants and 1 nonsynonymous variant were observed in the OATP-C and OAT3 genes, respectively [16].
• These parameters were comparable with those for hOAT1 and/or hOAT3 [12].
• The apparent Km values for hOAT2-, hOAT3- and hOAT4-mediated tetracycline uptakes were 439.9 +/- 23.0, 566.2 +/- 28.4 and 122.7 +/- 16.0 microM, respectively [17].
• The K(i) value of probenecid for hOAT3, but not for hOATP1B3, was significantly lower than the maximum unbound plasma concentration of probenecid at clinical dosages [13].
• In conclusion, these data indicate that MTX treatment down-regulates expression levels of Mrp2, Oat1 and Oat3, and its effects are recovered by leucovorin [18].

Analytical, diagnostic and therapeutic context of SLC22A8

• Molecular cloning and characterization of two novel human renal organic anion transporters (hOAT1 and hOAT3) [19].
• The native corresponding proteins of URAT1, OAT1 and OAT3, in human kidney can be recognized by their specific antibodies, respectively, with Western blot analysis and immunohistochemistry [20].
• Northern blot analysis revealed that hOAT3 mRNA is expressed in the kidney, brain, and skeletal muscle [21].
• The hOAT3 protein was shown to be localized in the basolateral membrane of renal proximal tubules and the hOAT3 gene was determined to be located on the human chromosome 11q12-q13.3 by fluorescent in situ hybridization analysis [21].
• Electrophoretic mobility shift assays demonstrated binding of the HNF1alpha/HNF1alpha homodimer or HNF1alpha/HNF1beta heterodimer to the hOAT3 promoter [4].

References