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OAT4 (SLC22A11)

Molecular structure and Tissue distribution
The organic anion transporter 4 is the only transporter that is specific for human and primates. The gene encoding OAT4, SLC22A11, is located on chromosome 11q13.1 and is paired with the gene for URAT1, SLC2212. The OAT4 protein shows all structural properties typical of OATs (12 transmembrane helices, with intracellular N- and C-terminus). Immunohistologically, OAT4 was detected in the apical membrane of proximal tubule cells in the kidneys and found to be expressed in placenta.

Interaction of OAT4 with endogenous compounds and drugs.
Human OAT4 possesses high affinity for sulfated steroid hormones Dehydroepi-androsterone sulfate and estrone-3-sulfate, with Km values of 0,6 µM and 1.0 µM, respectively. OAT4 also mediates the transport of prostaglandin E2, F and urate. Other endogenous compounds like  cholate, taurocholate, octanoate, succinate, estrone, 17ß-estradiol-3-sulfate inhibit OAT4 mediated Estron sulfate uptake. Glucurorenidated hormones e,g, 17ß-estradiol-3-D-glucuronide have no influence on OAT4 transport activity. In comparison to OAT1 or OAT3, OAT4 is an asymmetric carrier. It transports organic anions (e.g. p-aminohippurate, prototypical substrate of OATs) accumulated in the cell by OAT1 and OAT3 in the outward direction by exchanging against extracellular chloride ions. Urate and Estrone sulfate are taken up or reabsorbed by OAT4 from the ultrafiltrate in exchange for dicarboxylate or/and, hydroxyl ions. Therefore OAT4 provides an exit for endogens organic anions into the lumen. Due to its localization in the placenta, OAT4 allows the release of metabolites and toxic substrates from the fetus towards the mother, and also deliver sulfated steroid hormones from the mother for placental estrogen synthesis.
A relatively small number of drugs and exogenous compounds were tested for their interaction with OAT4. Only the following drugs (tetracycline, bumetanide, zidovudine, ketoprofen, sliycilate and methotrexate) are actively transported by OAT4. Several drugs such as antibiotics (cephaloridine, cefamandol), diuretics (acetazolamide, ethacrynat), NSAID (phenylbutazone piroxcam), antihpertensives (captopril), cytostatics (chlorambucil), statins (pravastatin) and uricosurics (probenecid) showed a significant inhibition of OAT4 mediated transport.

Figure 1 Concentration dependent OAT4 mediated estrone-sulfate uptake Figure 2 Inhibition of OAT4 mediated estrone-sulfate uptake by BSP

 

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