Figure 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.
OAT1 functions asorganic anion exchanger. 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 calledNaDC3 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 theS2 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]
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 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 tubule cells. 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]
Sincenucleoside analogs can build up in OAT1-positive cells and can inhibitmitochondrial replication, these drugs may lead to the depletion of mitochondria inside renalproximal tubules. Renalbiopsies have demonstrated the depletion of tubule cell mitochondria among individuals receiving antiviral therapy with tenofovir. The remaining mitochondria were enlarged anddysmorphic.[19]In vitro the antiviral drugs didanosine and zidovudine are more potent inhibitors ofmitochondrial 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 aherpes virus.[citation needed]
Stavudine, zidovudine andindinavir (IDV) cause a decrease in mitochondrialrespiration and 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 bephosphorylated 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 aprotease 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 notbrown 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 reversechirality compared to didanosine, stavudine, zidovudine, and naturalnucleosides. MitochondrialDNA polymerase may 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]
^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.
^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.doi:10.1016/S0022-3565(24)39144-X.PMID10945832.
^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.
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.Bibcode:1999BBRC..255..508R.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.Bibcode:2000BBRC..275..623B.doi:10.1006/bbrc.2000.3230.PMID10964714.
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.
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.
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.
