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OAT3 (SLC22A8)

Molecular structure and Tissue distribution
The organic anion transporter 3 (OAT3) is also cloned from several species. The gene for hOAT3 named SLC22A8, is paired with that of OAT1 and located on chromosome 11q12.3. The hOAT3 protein consists of 12 transmembrane helices as predicted by analysis of secondary structure algorithm and showed the intracellular localization of N- and C-terminus. Immunohistological studies showed the expression of OAT3 at the basolateral membrane of proximal tubule cells in human kidneys and in lower extent in brain, liver and adrenals.

Interaction of OAT3 with endogenous compounds and drugs
OAT3 interacts with a vast number of endogenous organic anions. Human OAT3 mediated transport of the following endogenous organic anions, mainly hormones cortisol prostaglandin E2 and F2α, conjugated hormones dehydroepiandrosterone sulfate (DHEAS), estrone sulfate and estradiol-17ß-gluconatehas been previously shown. The second messenger cAMP, the bile salt taurocholate, the Krebs’ cycle intermediate α-ketoglutarate and the purine metabolite urate are also actively transported by OAT3. Several endogenous substrates such as cholate, melatonin, and neurotransmitter metabolites are shown to inhibit the OAT3 facilitated transport of radioactive labeled substrate. The capacity of hOAT3 to transport steroid hormones functionally differentiates from hOAT1.

Several publications showed the human OAT3 mediated transport of numerous drugs, such as antibiotics (benzylpenicillin, tetracycline), diuretics (furosemide), NSAIDs (ibuprofen, indomethacin, salicylate), statins (pravastatin) histamin-Receptor2 blockers (cimetidine, ranitidine) and cytostatics (methotrexate). Inhibition studies are also performed to examine the interaction of OAT3 with other drugs belonging to antibiotics, diuretics, NSAID, anivirals, cytostatics and statin. The following drugs like antibiotics (cefadroxil, cephaloridine), diuretics (torasemide, bumetanide, chlorothiazide), NSAID (acetylsalicylate, diclofenac), antihpertensives (captopril, losartan), cytostatics  (chlorambucil, bendamustine), statins (pravastatin, fluvastatin) and uricosurics (probenecid, benzbromaron) showed a significant inhibition of OAT3 transport activity.

Figure 1 Concentration dependent OAT3 mediated estrone-sulfate uptake Figure 2 Inhibition of OAT3 mediated estrone-sulfate uptake by indomethacin

 

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