Abstract
This session was opened by GERHARD BURCKHARDT (Gottingen, Germany). He summarized role of organic anion transporters (OATs) in the uptake of drugs into renal cells1. OAT1 (SLC22A6) is located at the basolateral membrane of S2 proximal tubule epithelial cells of rat and human kidney. It exchanges intracellular -ketoglutarate against extracellular organic anions, thereby driving organic anion uptake against the prevailing electrochemical potential difference. In flounder renal OAT1, two positively charged, conserved amino acids (K394 and R478) have been identified to be essential for interaction with dicarboxylates. In all species OAT1 exhibits a broad substrate specificity and is responsible for uptake of most amphiphilic organic anions into proximal tubule cells. Besides classical organic anions, for example, p-aminohippurate, its substrate spectrum includes numerous drugs (such as, -lactam antibiotics, antiviral drugs), nephrotoxins (such as, ochratoxin A) and heavy metal chelators [for example, 2,3-dimercaptopropane-1-sulfonate (DMPS)]2,3. Closely related to OAT1 is OAT3 (SLC22A8), which exhibits a similar localization and similar polyspecific substrate transport properties as OAT1. However, OAT3 cannot exchange intracellular -ketoglutarate for extracellular organic anions. OAT2 (SLC22a7) and OAT4 are more distantly related to OAT1/OAT3. Although OAT2 and OAT4 are polyspecific transporters, they cannot mediate -ketoglutarate/organic anion exchange. OAT2 is expressed in the liver and also in the kidneys of female rats4. OAT4 may be localized at the apical membrane of human renal proximal tubule cells and may be involved in the excretion of organic anions into the urine. However, the multidrug resistance protein Mrp2 is responsible for ATP-dependent apical excretion of p-aminohippurate and probably also of other organic anions5. In summary, OATs are involved in renal drug excretion and play an important role in the pharmacokinetics and nephrotoxicity of renally eliminated drugs.
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