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.
Theorganic anion transporter 1(OAT1) also known assolute carrier family22 member 6(SLC22A6) is aproteinthat in humans is encoded by theSLC22A6gene.[2][3][4]It is a member of theorganic anion transporter(OAT) family of proteins. OAT1 is atransmembrane proteinthat is expressed in the brain, the placenta, the eyes,smooth muscles,and thebasolateral membraneofproximal tubularcells of the kidneys. It plays a central role inrenalorganic aniontransport. Along withOAT3,OAT1 mediates the uptake of a wide range of relatively small andhydrophilicorganic anions fromplasmainto thecytoplasmof the proximal tubular cells of thekidneys.From there, these substrates are transported into thelumenof thenephronsof the kidneys forexcretion.OAT1homologshave been identified inrats,mice,rabbits,pigs,flounders,andnematodes.[5]
Function
[edit]
OAT1 functions asorganic anionexchanger. When the uptake of one molecule of an organic anion is transported into a cell by an OAT1 exchanger, one molecule of anendogenousdicarboxylic acid(such asglutarate,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 calledNaDC3that 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 theS2 segmentof 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
[edit]Knownsubstratesof OAT1 includepara-aminohippurate(PAH),dicarboxylates,prostaglandins,cyclic nucleotides,urate,folate,diuretics,ACE inhibitors,antiviralagents,beta-lactam antibiotics,antineoplastics,mycotoxins,sulfate conjugates,glucuronideconjugates,cysteineconjugates,ochratoxin A,NSAIDs,mercapturic acidsanduremic toxins.[5]
Regulation
[edit]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
[edit]Nucleoside analogs are a class of antiviral drugs that work by inhibiting viral nucleic acid synthesis. The nucleoside analogsacyclovir(ACV),zidovudine(AZT),didanosine(ddI),zalcitabine(ddC),lamivudine(3TC),stavudine(d4T),trifluridine,[12]cidofovir,adefovir,[13]andtenofovir(TDF)[14]are substrates of the OAT1 transporter. This may result in the buildup of these drugs in theproximal tubulecells. At high concentrations, these drugs inhibitDNA replication.This, in turn, may impair the function of these cells and may be the cause of antiviral inducedFanconi 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
[edit]Sincenucleoside analogscan build up in OAT1-positive cells and can inhibitmitochondrialreplication, these drugs may lead to the depletion of mitochondria inside renalproximal tubules.Renalbiopsieshave demonstrated the depletion of tubule cell mitochondria among individuals receiving antiviral therapy with tenofovir. The remaining mitochondria were enlarged anddysmorphic.[19]In vitrothe antiviral drugs didanosine and zidovudine are more potent inhibitors ofmitochondrial DNAsynthesis 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 aherpes virus.[citation needed]
Stavudine, zidovudine andindinavir(IDV) cause a decrease in mitochondrialrespirationand an increase in mitochondrial mass infat 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 bephosphorylatedby 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 aprotease inhibitorand 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 notbrown fatcells.[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 reversechiralitycompared to didanosine, stavudine, zidovudine, and naturalnucleosides.MitochondrialDNA polymerasemay not recognize it as a substrate. Lamivudine is not toxic to mitochondriain 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
[edit]References
[edit]- ^Sekine T, Cha SH, Endou H (July 2000)."The multispecific organic anion transporter (OAT) family"(PDF).Pflügers Arch.440(3): 337–50.doi:10.1007/s004240000297.PMID10954321.S2CID32469988.
- ^Reid G, Wolff NA, Dautzenberg FM, Burckhardt G (Jan 1999). "Cloning of a human renal p-aminohippurate transporter, hROAT1".Kidney Blood Press Res.21(2–4): 233–7.doi:10.1159/000025863.PMID9762842.S2CID46811285.
- ^Lu R, Chan BS, Schuster VL (Mar 1999). "Cloning of the human kidney PAH transporter: narrow substrate specificity and regulation by protein kinase C".Am J Physiol.276(2 Pt 2): F295–303.doi:10.1152/ajprenal.1999.276.2.F295.PMID9950961.
- ^"Entrez Gene: SLC22A6 solute carrier family 22 (organic anion transporter), member 6".
- ^abcdSekine T, Miyazaki H, Endou H (February 2006). "Molecular physiology of renal organic anion transporters".Am. J. Physiol. Renal Physiol.290(2): F251–61.doi:10.1152/ajprenal.00439.2004.PMID16403838.
- ^abcGRCh38: Ensembl release 89: ENSG00000197901–Ensembl,May 2017
- ^abcGRCm38: 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.
- ^Stellmer F, Keyser B, Burckhardt BC, et al. (July 2007). "3-Hydroxyglutaric acid is transported via the sodium-dependent dicarboxylate transporter NaDC3".J. Mol. Med.85(7): 763–70.doi:10.1007/s00109-007-0174-5.PMID17356845.S2CID2922696.
- ^abcXu D, Wang H, You G (2016)."Posttranslational Regulation of Organic Anion Transporters by Ubiquitination: Known and Novel".Med Res Rev.36(5): 964–79.doi:10.1002/med.21397.PMC5147025.PMID27291023.
- ^Wada S, Tsuda M, Sekine T, Cha SH, Kimura M, Kanai Y, Endou H (September 2000). "Rat multispecific organic anion transporter 1 (rOAT1) transports zidovudine, acyclovir, and other antiviral nucleoside analogs".J. Pharmacol. Exp. Ther.294(3): 844–9.PMID10945832.
- ^Ho ES, Lin DC, Mendel DB, Cihlar T (March 2000)."Cytotoxicity of antiviral nucleotides adefovir and cidofovir is induced by the expression of human renal organic anion transporter 1".J. Am. Soc. Nephrol.11(3): 383–93.doi:10.1681/ASN.V113383.PMID10703662.
- ^Kohler JJ; Hosseini SH; Green E; Russ R; Santoianni R; Lewis w (April 2010)."OAT1 Knock-out Mice Define Its Role in Tenofovir Transport and Renal Proximal Tubular Mitochondrial Toxicity".FASEB J.24(1_MeetingAbstracts): Meeting abstracts, 1030.1.doi:10.1096/fasebj.24.1_supplement.1030.1.
- ^Nelson M, Azwa A, Sokwala A, Harania RS, Stebbing J (2008)."Fanconi syndrome and lactic acidosis associated with stavudine and lamivudine therapy".AIDS.22(11): 1374–6.doi:10.1097/QAD.0b013e328303be50.PMID18580619.S2CID5229576.
- ^Ahmad M (2006). "Abacavir-induced reversible Fanconi syndrome with nephrogenic diabetes insipidus in a patient with acquired immunodeficiency syndrome".J Postgrad Med.52(4): 296–7.PMID17102551.
- ^Vittecoq D, Dumitrescu L, Beaufils H, Deray G (August 1997)."Fanconi syndrome associated with cidofovir therapy".Antimicrob. Agents Chemother.41(8): 1846.doi:10.1128/AAC.41.8.1846.PMC164022.PMID9257778.
- ^Atta MG, Fine DM (March 2009). "Editorial comment: tenofovir nephrotoxicity--the disconnect between clinical trials and real-world practice".AIDS Read.19(3): 118–9.PMID19334329.
- ^Herlitz LC, Mohan S, Stokes MB, Radhakrishnan J, D'Agati VD, Markowitz GS (September 2010)."Tenofovir nephrotoxicity: acute tubular necrosis with distinctive clinical, pathological, and mitochondrial abnormalities".Kidney Int.78(11): 1171–1177.doi:10.1038/ki.2010.318.PMID20811330.
- ^Vidal F, Domingo JC, Guallar J, et al. (November 2006)."In vitro cytotoxicity and mitochondrial toxicity of tenofovir alone and in combination with other antiretrovirals in human renal proximal tubule cells".Antimicrob. Agents Chemother.50(11): 3824–32.doi:10.1128/AAC.00437-06.PMC1635212.PMID16940060.
- ^Viengchareun S, Caron M, Auclair M, et al. (2007)."Mitochondrial toxicity of indinavir, stavudine and zidovudine involves multiple cellular targets in white and brown adipocytes".Antivir. Ther. (Lond.).12(6): 919–29.doi:10.1177/135965350701200610.PMID17926646.S2CID25419054.
- ^abHonkoop P, de Man RA, Scholte HR, Zondervan PE, Van Den Berg JW, Rademakers LH, et al. (1997)."Effect of lamivudine on morphology and function of mitochondria in patients with chronic hepatitis B."Hepatology.26(1): 211–5.doi:10.1002/hep.510260128.PMID9214472.S2CID8029309.
- ^Ananworanich J, Nuesch R, Côté HC, Kerr SJ, Hill A, Jupimai T, et al. (2008)."Changes in metabolic toxicity after switching from stavudine/didanosine to tenofovir/lamivudine--a Staccato trial substudy".J Antimicrob Chemother.61(6): 1340–3.doi:10.1093/jac/dkn097.PMID18339636.
Further reading
[edit]- 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.doi:10.1152/ajprenal.1999.276.1.F122.PMID9887087.
- 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.doi:10.1006/bbrc.1998.9978.PMID10049739.
- 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.doi:10.1124/mol.56.3.570.PMID10462545.
- 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.doi:10.1006/bbrc.2000.3230.PMID10964714.
- 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.doi:10.1254/jjp.88.69.PMID11855680.
- 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.doi:10.1152/ajprenal.00290.2002.PMID12429554.
- 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.doi:10.1046/j.1523-1755.2003.00710.x.PMID12472777.
- 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.Bibcode:2002PNAS...9916899M.doi:10.1073/pnas.242603899.PMC139241.PMID12477932.
- 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.doi:10.1097/01.ASN.0000079040.55124.25.PMID12874449.
- 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.doi:10.1152/ajprenal.00326.2003.PMID14644751.S2CID7610758.
- 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.doi:10.1038/ng1285.PMID14702039.
- 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.doi:10.1074/jbc.M400197200.PMID14749323.
- 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.doi:10.1023/B:PHAM.0000012153.71993.cb.hdl:2433/144752.PMID14984259.S2CID28592120.
- 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.doi:10.1124/dmd.32.4.424.PMID15039295.
- 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.doi:10.1074/jbc.M404686200.PMID15145940.
- 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.doi:10.1111/j.1523-1755.2004.00726.x.PMID15200431.
- 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.doi:10.1097/01.ASN.0000135115.63412.A9.PMID15284288.
- 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.doi:10.1097/01213011-200504000-00003.PMID15864112.S2CID24148270.