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. [2] [3] [4] 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. [5]
SLC22A6 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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Aliases | SLC22A6 , HOAT1, OAT1, PAHT, ROAT1, Organic anion transporter 1, solute carrier family 22 member 6 | ||||||||||||||||||||||||||||||||||||||||||||||||||
External IDs | OMIM: 607582 MGI: 892001 HomoloGene: 16813 GeneCards: SLC22A6 | ||||||||||||||||||||||||||||||||||||||||||||||||||
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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. [5] 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. [10]
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. [5]
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. [5]
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. [11] 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. [11] 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, [11] sulfation, methylation, acetylation, and hydroxylation.
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, [12] cidofovir, adefovir, [13] and tenofovir (TDF) [14] 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, [15] didenosine, abacavir, adefovir, [16] cidofovir [17] 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. [18]
Since nucleoside analogs can build up in OAT1-positive cells and can inhibit mitochondrial replication, these drugs may lead to the depletion of mitochondria inside renal proximal tubules. Renal biopsies have demonstrated the depletion of tubule cell mitochondria among individuals receiving antiviral therapy with tenofovir. The remaining mitochondria were enlarged and dysmorphic. [19] In vitro the antiviral drugs didanosine and zidovudine are more potent inhibitors of mitochondrial DNA synthesis than tenofovir (ddI > AZT > TDF). [20] In its non-phosphorylated form, the drug acyclovir does not significantly inhibit mitochondrial DNA synthesis, unless the cell happens to be infected with a herpes virus. [ citation needed ]
Stavudine, zidovudine and indinavir (IDV) cause a decrease in mitochondrial respiration and an increase in mitochondrial mass in fat cells. Stavudine also causes severe mitochondrial DNA depletion. Combining zidovudine with stavudine does not increase the mitochondrial toxicity compared to stavudine alone. Both of these drugs must be phosphorylated by host enzymes before they become active. Zidovudine inhibits the phosphorylation of stavudine. This might reduce the toxicity of the combination. Using indinavir in combination with the other two drugs did not increase the toxicity of the combination. Indinavir is a protease inhibitor and works by a different mechanism than the other antiviral drugs. (d4T+AZT+IDV = d4T+AZT = d4T+IDV > AZT+IDV = AZT = IDV). All three of these drugs inhibit the expression of respiratory chain subunits (cytochrome c oxidase [CytOx]2 and CytOx4) in white fat cells but not brown fat cells. [21] Since stavudine and zidovudine are OAT1 substrates, they may have similar effects on proximal renal tubule cells as they do on fat cells.
Lamivudine has reverse chirality compared to didanosine, stavudine, zidovudine, and natural nucleosides. Mitochondrial DNA polymerase may not recognize it as a substrate. Lamivudine is not toxic to mitochondria in vivo . [22] Individuals who had been taking didanosine combined with stavudine exhibited improved mitochondrial function when they switched to lamivudine combined with tenofovir. [22] [23]
Mitochondrial toxicity of OAT1 substrates:
Zidovudine (ZDV), also known as azidothymidine (AZT), is an antiretroviral medication used to prevent and treat HIV/AIDS. It is generally recommended for use in combination with other antiretrovirals. It may be used to prevent mother-to-child spread during birth or after a needlestick injury or other potential exposure. It is sold both by itself and together as lamivudine/zidovudine and abacavir/lamivudine/zidovudine. It can be used by mouth or by slow injection into a vein.
Renal physiology is the study of the physiology of the kidney. This encompasses all functions of the kidney, including maintenance of acid-base balance; regulation of fluid balance; regulation of sodium, potassium, and other electrolytes; clearance of toxins; absorption of glucose, amino acids, and other small molecules; regulation of blood pressure; production of various hormones, such as erythropoietin; and activation of vitamin D.
The proximal tubule is the segment of the nephron in kidneys which begins from the renal pole of the Bowman's capsule to the beginning of loop of Henle. It can be further classified into the proximal convoluted tubule (PCT) and the proximal straight tubule (PST).
Reverse-transcriptase inhibitors (RTIs) are a class of antiretroviral drugs used to treat HIV infection or AIDS, and in some cases hepatitis B. RTIs inhibit activity of reverse transcriptase, a viral DNA polymerase that is required for replication of HIV and other retroviruses.
Lamivudine, commonly called 3TC, is an antiretroviral medication used to prevent and treat HIV/AIDS. It is also used to treat chronic hepatitis B when other options are not possible. It is effective against both HIV-1 and HIV-2. It is typically used in combination with other antiretrovirals such as zidovudine and abacavir. Lamivudine may be included as part of post-exposure prevention in those who have been potentially exposed to HIV. Lamivudine is taken by mouth as a liquid or tablet.
Tenofovir disoproxil, sold under the trade name Viread among others, is a medication used to treat chronic hepatitis B and to prevent and treat HIV/AIDS. It is generally recommended for use with other antiretrovirals. It may be used for prevention of HIV/AIDS among those at high risk before exposure, and after a needlestick injury or other potential exposure. It is sold both by itself and together in combinations such as emtricitabine/tenofovir, efavirenz/emtricitabine/tenofovir, and elvitegravir/cobicistat/emtricitabine/tenofovir. It does not cure HIV/AIDS or hepatitis B. It is available by mouth as a tablet or powder.
Acute tubular necrosis (ATN) is a medical condition involving the death of tubular epithelial cells that form the renal tubules of the kidneys. Because necrosis is often not present, the term acute tubular injury (ATI) is preferred by pathologists over the older name acute tubular necrosis (ATN). ATN presents with acute kidney injury (AKI) and is one of the most common causes of AKI. Common causes of ATN include low blood pressure and use of nephrotoxic drugs. The presence of "muddy brown casts" of epithelial cells found in the urine during urinalysis is pathognomonic for ATN. Management relies on aggressive treatment of the factors that precipitated ATN. Because the tubular cells continually replace themselves, the overall prognosis for ATN is quite good if the underlying cause is corrected, and recovery is likely within 7 to 21 days.
Probenecid, also sold under the brand name Probalan, is a medication that increases uric acid excretion in the urine. It is primarily used in treating gout and hyperuricemia.
Lamivudine/zidovudine, sold under the brand name Combivir among others, is a fixed-dose combination antiretroviral medication used to treat HIV/AIDS. It contains two antiretroviral medications, lamivudine and zidovudine. It is used together with other antiretrovirals. It is taken by mouth twice a day.
Cephaloridine is a first-generation semisynthetic derivative of antibiotic cephalosporin C. It is a Beta lactam antibiotic, like penicillin. Its chemical structure contains 3 cephems, 4 carboxyl groups and three pyridinium methyl groups.
Multidrug resistance-associated protein 2 (MRP2) also called canalicular multispecific organic anion transporter 1 (cMOAT) or ATP-binding cassette sub-family C member 2 (ABCC2) is a protein that in humans is encoded by the ABCC2 gene.
Solute carrier family 26 member 6 is a protein that in humans is encoded by the SLC26A6 gene. It is an anion-exchanger expressed in the apical membrane of the kidney proximal tubule, the apical membranes of the duct cells in the pancreas, and the villi of the duodenum.
Solute carrier family 22 member 8, or organic anion transporter 3 (OAT3), is a protein that in humans is encoded by the SLC22A8 gene.
Solute carrier family 22, member 12, also known as SLC22A12 and URAT1, is a protein which in humans is encoded by the SLC22A12 gene.
A carboxylate transporter is a membrane transport protein that transports carboxylate.
Solute carrier family 22 member 9 is a protein that in humans is encoded by the SLC22A9 gene.
Discovery and development of nucleoside and nucleotide reverse-transcriptase inhibitors began in the 1980s when the AIDS epidemic hit Western societies. NRTIs inhibit the reverse transcriptase (RT), an enzyme that controls the replication of the genetic material of the human immunodeficiency virus (HIV). The first NRTI was zidovudine, approved by the U.S. Food and Drug Administration (FDA) in 1987, which was the first step towards treatment of HIV. Six NRTI agents and one NtRTI have followed. The NRTIs and the NtRTI are analogues of endogenous 2´-deoxy-nucleoside and nucleotide. Drug-resistant viruses are an inevitable consequence of prolonged exposure of HIV-1 to anti-HIV drugs.
Fanconi syndrome or Fanconi's syndrome is a syndrome of inadequate reabsorption in the proximal renal tubules of the kidney. The syndrome can be caused by various underlying congenital or acquired diseases, by toxicity, or by adverse drug reactions. It results in various small molecules of metabolism being passed into the urine instead of being reabsorbed from the tubular fluid. Fanconi syndrome affects the proximal tubules, namely, the proximal convoluted tubule (PCT), which is the first part of the tubule to process fluid after it is filtered through the glomerulus, and the proximal straight tubule, which leads to the descending limb of loop of Henle.
The anion exchanger family is a member of the large APC superfamily of secondary carriers. Members of the AE family are generally responsible for the transport of anions across cellular barriers, although their functions may vary. All of them exchange bicarbonate. Characterized protein members of the AE family are found in plants, animals, insects and yeast. Uncharacterized AE homologues may be present in bacteria. Animal AE proteins consist of homodimeric complexes of integral membrane proteins that vary in size from about 900 amino acyl residues to about 1250 residues. Their N-terminal hydrophilic domains may interact with cytoskeletal proteins and therefore play a cell structural role. Some of the currently characterized members of the AE family can be found in the Transporter Classification Database.
Stephen Henry Wright is an American physiologist. He is primarily known for his work on the mechanisms of organic solute transport in kidney tubules, but he is also known for work to describe transport of organic solutes across epithelial membranes by marine invertebrates.