Organic anion transporter 1

The organic anion transporter 1 (OAT1) also known as solute carrier family 22 member 6 (SLC22A6) is a protein that in humans is encoded by the SLC22A6 gene. It is a member of the organic anion transporter (OAT) family of proteins. OAT1 is a transmembrane protein that is expressed in the brain, the placenta, the eyes, smooth muscles, and the basolateral membrane of proximal tubular cells of the kidneys. It plays a central role in renal organic anion transport. Along with OAT3, OAT1 mediates the uptake of a wide range of relatively small and hydrophilic organic anions from plasma into the cytoplasm of the proximal tubular cells of the kidneys. From there, these substrates are transported into the lumen of the nephrons of the kidneys for excretion. OAT1 homologs have been identified in rats, mice, rabbits, pigs, flounders, and nematodes.

Function

OAT1 functions as organic anion exchanger. When the uptake of one molecule of an organic anion is transported into a cell by an OAT1 exchanger, one molecule of an endogenous dicarboxylic acid (such as glutarate, ketoglutarate, etc.) is simultaneously transported out of the cell. As a result of the constant removal of endogenous dicarboxylic acid, OAT1-positive cells are at risk of depleting their supply of dicarboxylates. Once the supply of dicarboxylates is depleted, the OAT1 transporter can no longer function. To prevent the loss of endogenous dicarboxylates, OAT1-positive cells also express a sodium-dicarboxylate cotransporter called NaDC3 that transports dicarboxylates back into the OAT1-positive cell. Sodium is required to drive this process. In the absence of a sodium gradient across the cell membrane, the NaDC3 cotransporter ceases to function, intra-cellular dicarboxylates are depleted, and the OAT1 transporter also grinds to a halt. The renal organic anion transporters OAT1, OAT3, OATP4C1, MDR1, MRP2, MRP4 and URAT1 are expressed in the S2 segment of the proximal convoluted tubules of the kidneys. OAT1, OAT3, and OATP4C1 transport small organic anions from the plasma into the S2 cells. MDR1, MRP2, MRP4 and URAT1 then transports these organic anions from the cytoplasm of the S2 cells into the lumen of the proximal convoluted tubules. These organic anions are then excreted in the urine.

Substrates Known substrates of OAT1 include para-aminohippurate (PAH), dicarboxylates, prostaglandins, cyclic nucleotides, urate, folate, diuretics, ACE inhibitors, antiviral agents, beta-lactam antibiotics, antineoplastics, mycotoxins, sulfate conjugates, glucuronide conjugates, cysteine conjugates, ochratoxin A, NSAIDs, mercapturic acids and uremic toxins.

Regulation Alterations in the expression and function of OAT1 play important roles in intra- and inter-individual variability of the therapeutic efficacy and the toxicity of many drugs. As a result, the activity of OAT1 must be under tight regulation so as to carry out their normal functions. The regulation of OAT transport activity in response to various stimuli can occur at several levels such as transcription, translation, and posttranslational modification. Posttranslational regulation is of particular interest, because it usually happens within a very short period of time (minutes to hours) when the body has to deal with rapidly changing amounts of substances as a consequence of variable intake of drugs, fluids, or meals as well as metabolic activity. Post-translational modification is a process where new functional group(s) are conjugated to the amino acid side chains in a target protein through reversible or irreversible biochemical reactions. The common modifications include glycosylation, phosphorylation, ubiquitination, sulfation, methylation, acetylation, and hydroxylation.

Antiviral induced Fanconi syndrome Nucleoside analogs are a class of antiviral drugs that work by inhibiting viral nucleic acid synthesis. The nucleoside analogs acyclovir (ACV), zidovudine (AZT), didanosine (ddI), zalcitabine (ddC), lamivudine (3TC), stavudine (d4T), trifluridine, cidofovir, adefovir, and tenofovir (TDF) are substrates of the OAT1 transporter. This may result in the buildup of these drugs in the proximal tubule cells. At high concentrations, these drugs inhibit DNA replication. This, in turn, may impair the function of these cells and may be the cause of antiviral induced Fanconi syndrome. The use of stavudine, didenosine, abacavir, adefovir, cidofovir and tenofovir has been associated with Fanconi syndrome. Clinical features of tenofovir-induced Fanconi syndrome include glycosuria in the setting of normal serum glucose levels, phosphate wasting with hypophosphatemia, proteinuria (usually mild), acidosis, and hypokalemia, with or without acute renal failure.

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