Organic anion transporter 1
Schematic representation of transmembrane proteins:
1. a membrane protein with one transmembrane domain
2. a membrane protein with three transmembrane domains
3. OAT1 is believed to have twelve transmembrane domains.[1]
The membrane is represented in light brown.
The organic anion transporter 1 (OAT1) also known as
Function
| SLC22A6 | |||
|---|---|---|---|
| Identifiers | |||
Gene ontology | |||
| Molecular function | |||
| Cellular component | |||
| Biological process |
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| Sources:Amigo / QuickGO | |||
Ensembl | |||||||||
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| UniProt | |||||||||
| RefSeq (mRNA) | |||||||||
| RefSeq (protein) | |||||||||
| Location (UCSC) | Chr 11: 62.94 – 62.98 Mb | Chr 19: 8.6 – 8.61 Mb | |||||||
| PubMed search | [8] | [9] | |||||||
| View/Edit Human | View/Edit Mouse |
OAT1 functions as
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,
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]
Substrates
Known
uremic toxins.[5]
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.[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.
Antiviral induced Fanconi syndrome
Nucleoside analogs are a class of antiviral drugs that work by inhibiting viral nucleic acid synthesis. The nucleoside analogs
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]
Mitochondrial inhibition
Since
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
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
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:
- in vitro:
- d4T+AZT = d4T > AZT
- ddI > AZT > TDF > ACV
- in vivo
- d4T > AZT
- ddI > AZT > TDF
- d4T + ddI > 3TC + TDF
See also
References
- S2CID 32469988.
- S2CID 46811285.
- PMID 9950961.
- ^ "Entrez Gene: SLC22A6 solute carrier family 22 (organic anion transporter), member 6".
- ^ PMID 16403838.
- ^ a b c GRCh38: Ensembl release 89: ENSG00000197901 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000024650 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- S2CID 2922696.
- ^ PMID 27291023.
- PMID 10945832.
- PMID 10703662.
- .
- S2CID 5229576.
- PMID 17102551.
- PMID 9257778.
- PMID 19334329.
- PMID 20811330.
- PMID 16940060.
- S2CID 25419054.
- ^ S2CID 8029309.
- PMID 18339636.
Further reading
- Hosoyamada M, Sekine T, Kanai Y, Endou H (1999). "Molecular cloning and functional expression of a multispecific organic anion transporter from human kidney". Am. J. Physiol. 276 (1 Pt 2): F122–8. PMID 9887087.
- Race JE, Grassl SM, Williams WJ, Holtzman EJ (1999). "Molecular cloning and characterization of two novel human renal organic anion transporters (hOAT1 and hOAT3)". Biochem. Biophys. Res. Commun. 255 (2): 508–14. PMID 10049739.
- Cihlar T, Lin DC, Pritchard JB, et al. (1999). "The antiviral nucleotide analogs cidofovir and adefovir are novel substrates for human and rat renal organic anion transporter 1". Mol. Pharmacol. 56 (3): 570–80. PMID 10462545.
- Bahn A, Prawitt D, Buttler D, et al. (2000). "Genomic structure and in vivo expression of the human organic anion transporter 1 (hOAT1) gene". Biochem. Biophys. Res. Commun. 275 (2): 623–30. PMID 10964714.
- Babu E, Takeda M, Narikawa S, et al. (2002). "Human organic anion transporters mediate the transport of tetracycline". Jpn. J. Pharmacol. 88 (1): 69–76. PMID 11855680.
- Burckhardt BC, Brai S, Wallis S, et al. (2003). "Transport of cimetidine by flounder and human renal organic anion transporter 1". Am. J. Physiol. Renal Physiol. 284 (3): F503–9. PMID 12429554.
- Ichida K, Hosoyamada M, Kimura H, et al. (2004). "Urate transport via human PAH transporter hOAT1 and its gene structure". Kidney Int. 63 (1): 143–55. PMID 12472777.
- Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. PMID 12477932.
- Wolff NA, Thies K, Kuhnke N, et al. (2004). "Protein kinase C activation downregulates human organic anion transporter 1-mediated transport through carrier internalization". J. Am. Soc. Nephrol. 14 (8): 1959–68. PMID 12874449.
- Sauvant C, Hesse D, Holzinger H, et al. (2004). "Action of EGF and PGE2 on basolateral organic anion uptake in rabbit proximal renal tubules and hOAT1 expressed in human kidney epithelial cells". Am. J. Physiol. Renal Physiol. 286 (4): F774–83. S2CID 7610758.
- Ota T, Suzuki Y, Nishikawa T, et al. (2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs". Nat. Genet. 36 (1): 40–5. PMID 14702039.
- Tanaka K, Xu W, Zhou F, You G (2004). "Role of glycosylation in the organic anion transporter OAT1". J. Biol. Chem. 279 (15): 14961–6. PMID 14749323.
- Sakurai Y, Motohashi H, Ueo H, et al. (2004). "Expression levels of renal organic anion transporters (OATs) and their correlation with anionic drug excretion in patients with renal diseases". Pharm. Res. 21 (1): 61–7. S2CID 28592120.
- Bahn A, Ebbinghaus C, Ebbinghaus D, et al. (2005). "Expression studies and functional characterization of renal human organic anion transporter 1 isoforms". Drug Metab. Dispos. 32 (4): 424–30. PMID 15039295.
- Hong M, Zhou F, You G (2004). "Critical amino acid residues in transmembrane domain 1 of the human organic anion transporter hOAT1". J. Biol. Chem. 279 (30): 31478–82. PMID 15145940.
- Zalups RK, Aslamkhan AG, Ahmad S (2005). "Human organic anion transporter 1 mediates cellular uptake of cysteine-S conjugates of inorganic mercury". Kidney Int. 66 (1): 251–61. PMID 15200431.
- Zalups RK, Ahmad S (2004). "Homocysteine and the renal epithelial transport and toxicity of inorganic mercury: role of basolateral transporter organic anion transporter 1". J. Am. Soc. Nephrol. 15 (8): 2023–31. PMID 15284288.
- Fujita T, Brown C, Carlson EJ, et al. (2005). "Functional analysis of polymorphisms in the organic anion transporter, SLC22A6 (OAT1)". Pharmacogenet. Genomics. 15 (4): 201–9. S2CID 24148270.