Organic anion transporters

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Structure of rat organic anion transporter 1 (OAT1) PDB code 8sdu

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Organic Anion Transporters, commonly known as OATs, are a subfamily of the solute carrier 22 (SLC22) transporters family, which also includes organic cation transporters (OCTs) and organic carnitine transporters (OCTNs). Moreover, they are included in the major facilitator superfamily (MFS) to whom OATs share many structural characteristics. OAT subfamily is composed of 10 transmembrane proteins (Figure 1) that play a vital role in transporting negatively charged organic compounds across cell membranes in living organisms. These transmembrane proteins are composed of about 540-560 aa comprising 12 transmembrane domains [1]

They are a family of 10 transmembrane proteins that play a vital role in transporting negatively charged organic compounds across cell membranes in living organisms. OATs are localized on the physiological barriers of multiple tissues, such as kidney, liver, olfactory mucosa, brain, retina, and placenta [2].

The principal OAT members are expressed in renal proximal tubule, both on the basolateral and on the apical membrane. They stand as important mediators in the active process of renal elimination and reabsorption. Because of the importance of OATs in disposition of many important clinical drugs and in various physio-pathological processes, numerous efforts have been made to uncover molecular and cellular mechanisms that contribute to the regulation of OATs [3].

Figure 1: stucture of OAT

HistoryHistory

The OAT pathway has been the subject of much investigation, particularly from the viewpoint of kidney physiology, over many decades. In the 1940s, Homer Smith suggested that a substituted hippuric acid derivative, p-aminohippuric acid (PAH), might be a suitable tracer for tubule excretion. PAH is a high-affinity substrate and is almost completely extracted by the renal Organic Anion Transport system during a single pass through the kidney when its serum concentration is low[1]. Thus, PAH clearance has been used to estimate renal plasma flow, and the renal organic anion transporter has been alternatively called PAH transporter. A prominent feature of the PAH transporter is that it interacts with and transports a variety of organic anions with unrelated chemical structures. Various endogenous organic anions, uremic substances, drugs, and environmental compounds have been assumed to be substrates of the PAH transporter. In 1997, the PAH transporter was isolated by several groups using expression cloning methods and designated OAT1. Subsequently, several organic anion transporting proteins have been identified at both sides of the renal proximal tubules and our knowledge of organic anion transporter systems has been increased[3].

During World War II, it was realized that penicillin was being rapidly excreted by the kidney through an organic acid transport system. As a strategy to slow the excretion of penicillin in the context of limited availability of antibiotics, the uricosuric agent probenecid (benemid) was used to competitively inhibit the excretion of penicillin when the two drugs were administered together. This was also found to affect PAH transport. Probenecid eventually became the standard inhibitor of the classical organic anion transporter system; indeed, the system was, for many years, operationally defined by the effect of probenecid. With the availability of a prototypical tracer (PAH) and what was perceived as a specific inhibitor (probenecid), the role of the “classical” organic anion transport pathway in the excretion of many drugs became well established in the subsequent decades [1].

SLC22 and OAT familySLC22 and OAT family

The SLC22 family encompasses various types of transporters, including organic cation transporters (OCTs), carnitine transporters (OCTNs), and organic anion transporters (OATs). Functionally, members of the SLC22 family operate diversely: serving as uniporters facilitating facilitated diffusion bidirectionally (OCTs), engaging in anion exchange (OAT1, OAT3, and URAT1), and operating as Na+/L- carnitine cotransporters (OCTN2). Their roles involve the absorption and/or elimination of drugs, foreign substances, and naturally occurring compounds in the intestines, liver, and/or kidneys. Among their endogenous substrates are monoamine neurotransmitters, choline, L-carnitine, α-ketoglutarate, cAMP, cGMP, prostaglandins, and urate. Additionally, they contribute to homeostasis in the brain and heart [4].

OAT familyOAT family

The Organic Anion Transporter family is a subgroup of integral membrane proteins categorized within this larger SLC22 transporter family. They are primarily expressed in tissues involved in the absorption, excretion, and distribution of molecules within the body, such as the kidneys, liver, intestines, and the blood-brain barrier. The ten members are the following:

  • OAT1 (SLC22A6). Secondary active transporter that functions as a Na+-independent organic anion (OA)/dicarboxylate antiporter where the uptake of one molecule of OA into the cell is coupled with an efflux of one molecule of intracellular dicarboxylate such as 2-oxoglutarate or glutarate. Mediates the uptake of OA across the basolateral side of proximal tubule epithelial cells, thereby contributing to the renal elimination of endogenous OA from the systemic circulation into the urine [5].
  • OAT2 (SLC22A7). Functions as a Na+-independent bidirectional multispecific transporter. Contributes to the renal and hepatic elimination of endogenous organic compounds from the systemic circulation into the urine and bile, respectively [6].
  • OAT3 (SLC22A8). Functions as an organic anion/dicarboxylate exchanger that couples organic anion uptake indirectly to the sodium gradient. Transports organic anions such as estrone 3-sulfate (ES) and urate in exchange for dicarboxylates such as glutarate or ketoglutarate (2-oxoglutarate) and plays an important role in the excretion of endogenous and exogenous organic anions, especially from the kidney and the brain [7].
  • OAT4 (SLC22A11). Antiporter that mediates the transport of conjugated steroids and other specific organic anions at the basal membrane of syncytiotrophoblast and at the apical membrane of proximal tubule epithelial cells, in exchange for anionic compounds [8].
  • OAT5 (SLC22A19) primarily located in the kidneys, is under investigation for its role in transporting organic anions, with specific substrates still being characterized.
  • OAT6 (SLC22A20) found in the kidneys and other tissues, is currently under active research to understand its specific functions and substrates.
  • OAT7 (SLC22A9) expressed in the liver, kidneys, and other tissues, is implicated in the transport of organic anions, but further characterization is ongoing.
  • OAT8 (SLC22A11) found in the liver and other tissues, is involved in the hepatic uptake and clearance of various substrates, particularly drugs.
  • OAT9 (SLC22A24) predominantly located in the kidneys, has a role in transporting organic anions, but specific functions and substrates are still being investigated.
  • OAT10 (SLC22A25) expressed in the kidneys, is currently being researched to understand its specific role in organic anion transport.

FunctionFunction

OATs are a key players for the translocation of various substances into and out of cells, such as odorants, cyclic nucleotides, protaglandins, conjugated sex steroids, metabolites, uremic toxins, vitamin-related metabolites or antioxidants; as well as a variety of important clinical therapies, including antivirals, anticancer drugs, antibiotics, antihypertensives and anti-inflammatories. They are also critical in absorption, distribution, metabolism, and elimination (ADME) of clinical therapeutics, thus affecting the pharmacokinetics and pharmacodynamics of the drug profile [1].

  • Elimination of waste products: OATs are involved in the elimination of metabolites and waste products from the body, enabling their excretion through urine. Also, they excrete toxic substances and foreign chemicals to maintain homeostasis and prevent harm. Here they include antivirals, anti-cancer drugs, antibiotics, anti-hypertensives, and anti-inflammatories or toxic substances[3].
  • Intestine absorption regulation: contribute to the absorption of essential nutrients such as organic acids and other compounds from the intestinal lumen into the epithelial cells, facilitating their distribution throughout the body[1].
  • Drug response: OATs have a wide range of substrate recognition including both physiological/endogenous substrates and their metabolites and xenobiotic molecules such as environmental toxins and therapeutic drugs. This has significant implications in pharmacology and can impact the effectiveness and toxicity of medications[3].

In summary, the primary function of OATs is to facilitate the transport of a variety of organic anionic compounds, including waste products, nutrients, and drugs, across cell membranes. This is essential for maintaining organism homeostasis and has significant implications in the elimination of metabolic waste and drug response.

StructureStructure

Figure 2: Molecular dynamics simulation of OAT1

The OAT family are transmembrane proteins of about 550 amino acids with intracellular and (TMDs). The transporter has 2 large loops: an one between TMD1/2 and an one between TMD6/7[3]. Three highly conserved regions allow for substrate specificity and the activity of the transporter in this protein: the first is the loop between TMD1/2, which mediates homo-oligomerization[4] and contains several ; the second is the intracellular loop between TMD6/7, which has phosphorylation sites and is involved in transcriptional regulation[4]; and the third is domains 9 and 10[3].

Among the different subtypes of OATs, the main structural differences are the number of phosphorylation sites (where, depending on the subtype, protein kinases A and C, casein kinase II, and tyrosine kinase can bind) and glycosylation sites, while maintaining the general structure among all members. The subtype that differs from the others most is OAT4, which possesses three C-terminus amino acids (threonine, serine, and leucine) that together form a PDZ binding motif. This motif is essential for the correct targeting and maintenance of the transporter in the renal cell's apical cell membrane [9].

Since the crystal structure of these transporters is yet unavailable, the studies carried out to observe the opening and closing mechanism have been performed on transporters homologous to these [10]. A transporter tilt that may be involved in the opening and closing of the transporter has been found in a molecular dynamics simulation for OAT1 based on the glycerol-3-phosphate transporter (GlpT). The opening of the carrier from the intracellular side of the membrane is depicted in this model, which displays the transporter's activity during a 100 ns period. Due to the brief duration of observation, it is not fully opened, but this tilting process may explain the initial stages of organic anion transport[11].

Figure 2A shows the change in the conformation of the zone closest to the extracellular face, showing it at 40ns in yellow and at 90ns in black (Figure 2Aa). This simulation illustrates how the distance between the residues of SER139 and MET358 increases with time, as seen in Figures 2Ab and 2Ac[11]. Figure 2B shows the change in the conformation of the zone closest to the intracellular face, with, as before, the structure at 40ns in yellow and at 94ns in black. In contrast to the extracellular zone, the distance between the residues (in this case VAL211 and GLY446) decreases with time (Figures 2Bb and 2Bc)[11]. Thus, in a simplified scheme showing only the 4 helices that participate in the spin, the model would be shown as in Figure 2C, observing, once again, in yellow the conformation at 40ns and in black at 94ns[11]. According to the results obtained in this model, the activation of the transporter would occur through the closure of the intracellular zone and the opening of the extracellular zone as seen in the simulations. Still, in order to examine this action more precisely, more models need to be created and the crystal structure of the transporter needs to be determined.

Mechanism of actionMechanism of action

OATs are secondary active transporters, utilizing the energy stored in the electrochemical gradient of specific ions (like sodium or potassium) established by primary active transporters such as ATPases [12]. The detailed breakdown of their mechanism is:

1. Substrate Binding. OATs recognize and bind to a wide array of organic anions, including endogenous substances like hormones (e.g., prostaglandins) and exogenous compounds such as drugs (e.g., antibiotics, NSAIDs). OATs bind substrates through interactions involving electrostatic forces, hydrogen bonds, and hydrophobic interactions between the transporter and the substrate molecule[10].

2. Conformational Changes. Upon substrate binding, the OAT undergoes conformational changes that allow it to transport the substrate across the cell membrane. These changes facilitate the movement of the substrate from the extracellular space into the cell or vice versa [13]. The typical domains or regions within OATs that commonly undergo conformational changes are:

  • Transmembrane Domains (TMDs): these domains span the lipid bilayer multiple times and contain the substrate-binding sites. Conformational changes in these regions occur upon substrate binding, altering their configuration to enable the transport of the substrate across the membrane.
  • Extracellular and Intracellular Loops: these regions connect the transmembrane segments and play a role in substrate recognition, binding, and transport. Conformational changes in these loops occur as part of the overall structural rearrangement necessary for substrate translocation.
  • Gate Domains or Gates: some transporters have specific gate domains or gating mechanisms that control access to the substrate-binding sites. Conformational changes in these gate domains upon substrate binding allow the transporter to open or close, regulating the entry or exit of substrates.
  • Cytosolic Domains: regions facing the cell's interior may also undergo conformational changes. These cytosolic domains often interact with cellular components or signaling molecules, modulating the transporter's activity or facilitating intracellular trafficking.

3. Transport Process: OATs primarily work through a process called facilitated diffusion or exchange transport. They utilize the pre-existing electrochemical gradient of ions, typically sodium ions, established by ion pumps or cotransporters, as the driving force for substrate movement. By harnessing this gradient, OATs can transport substrates following the concentration gradient, moving them from areas of high concentration to low concentration[12].

Mechanism regulationMechanism regulation

The regulation of Organic Anion Transporters (OATs) involves complex mechanisms that control their activity, expression levels, and localization within cells. These regulatory processes impact the transport of organic anions across cell membranes, influencing drug disposition, metabolic functions, and physiological homeostasis [3]. The main regulation mechanisms regulating OATs are:

  • Transcriptional Regulation. The expression of OAT genes is tightly controlled at the transcriptional level. Various transcription factors, such as nuclear receptors (e.g., PPARs - Peroxisome Proliferator-Activated Receptors), hormone receptors, and cytokine-induced signaling pathways, can modulate the expression of OAT genes in response to different stimuli. For instance, nuclear receptors play a role in regulating OAT expression in the liver and kidneys in response to changes in metabolic status.
  • Post-Transcriptional and Post-Translational Modifications. After transcription, various mechanisms regulate OAT activity post-transcriptionally and post-translationally. This includes processes like alternative splicing, mRNA stability, and protein modifications (e.g., phosphorylation, glycosylation, ubiquitination) that can influence transporter activity, stability, and localization within the cell.
  • Cellular Trafficking and Membrane Insertion. Regulation involves controlling the trafficking of OAT proteins within the cell and their insertion into the plasma membrane. Intracellular compartments, such as endosomes, lysosomes, and the endoplasmic reticulum, play roles in the sorting and trafficking of OAT proteins to their functional locations in the cell membrane. Regulation of these trafficking pathways affects the number of transporters available for substrate transport.
  • Modulation by Signaling Pathways. Various signaling pathways, including those involving protein kinases, phosphatases, and G-protein-coupled receptors (GPCRs), can modulate OAT activity. Activation or inhibition of these signaling cascades can lead to changes in transporter function through phosphorylation, dephosphorylation, or alterations in transporter affinity for substrates.
  • Drug-Induced Regulation. Some drugs can regulate OAT activity either by acting as substrates, inhibitors, or inducers of transporter expression. For example, certain medications may upregulate or downregulate OAT expression or function, thereby influencing their own pharmacokinetics or altering the disposition of co-administered drugs.

Drug interactionsDrug interactions

OATs are integral for the elimination and reabsorption of endogenous substances like hormones or metabolites, and xenobiotics (foreign compounds), including numerous drugs [14]. They play a vital role in pharmacokinetics, impacting drug absorption, distribution, metabolism, and excretion within the body. Therefore, drug interactions involving Organic Anion Transporters (OATs) are significant in pharmacology. Some important aspects of drug interactions involving OATs are[15]:

  • Substrate Competition: Drugs that are substrates for OATs may compete for binding sites on these transporters. This competition can lead to altered uptake or excretion of medications, affecting their concentrations in the body. For example, multiple drugs competing for transport via OATs may lead to reduced renal excretion of these drugs, potentially increasing their plasma concentrations and the risk of toxicity.
  • Inhibition and Induction: Some drugs can inhibit OAT activity, reducing the transport of co-administered drugs that utilize these transporters. On the other hand, certain medications may induce the expression of OATs, increasing their activity and potentially enhancing the elimination of other drugs.
  • Drug-Drug Interactions: Co-administration of medications that interact with OATs can result in drug-drug interactions. OATs have a wide spectrum of substrate recognition, therefore when administered together, different drugs may interact—either in a competitive or non-competitive way—with the same transporters, which can lead to mutually affecting each other’s pharmacokinetic profiles[3]. For instance, probenecid, known to inhibit OATs, can affect the renal excretion of various drugs, leading to increased plasma concentrations of co-administered drugs that are substrates for OATs[16].
  • Individual Variability: Genetic variations in OAT genes can lead to differences in transporter activity among individuals, affecting drug responses and susceptibility to drug interactions. Some individuals may be more susceptible to certain drug interactions due to genetic factors influencing OAT function.

Understanding the diversity within the OAT family, including their tissue distribution, substrate specificity, and regulatory mechanisms, is crucial in pharmacology and drug development. Manipulating the interactions with these transporters can have significant implications for drug efficacy, toxicity, and overall therapeutic outcomes. Some examples of drugs that interact with specific members of the Organic Anion Transporter (OAT) family are: probenecid (OAT1), furosemide (OAT2), cidofovir (OAT3), methotrexate (OAT3), indomethacin (OAT4)[13]...

Inhibitors and activatorsInhibitors and activators

  • Probenecid: is responsible for blocking these transporters which are found in the membrane of the proximal tubule and filter many substances from the blood to be secreted in the urine [17]. This drug prevents certain substances from being excreted in the urine, which may mediate the elimination time of these substances and prolongs the retention of certain compounds in the urine, which may be of clinical use when sought [17]. However, its inhibition can be a double-edged sword, as it can cause higher systemic toxicity by exposing the whole body to a drug for a prolonged time [3].
  • Indomethacin: is used for reducing fever, inflammation and pain. It is a nonsteroidal anti-inflammatory drug and an increase of its dose causes bleeding and ulceration of the intestine, which should be reduced by dose and side effects during treatment[18]. It can interfere with the elimination of certain drugs and metabolites in the kidney.
  • Quinapril: is used to treat hypertension, is a substrate of OAT3, and has been shown to increase blood levels and decrease renal clearance of indoxyl sulfate, a uremic toxin that is a substrate of OAT1, OAT3 and OAT4. This may suggest that quinapril competes with indoxyl sulfate for OAT3, thus decreasing the excretion of the toxin via the transporter [3].
  • Lansoprazole: inhibited OAT3, thus decreased the renal uptake and elimination of pemetrexed, and eventually increased hematologic toxicity in patients. In a clinical study of patients with non-small cell lung cancer, hematologic toxicity caused by pemetrexed was amplified when lansoprazole was co-administered [3].
  • Omeprazol: It is a proton pump inhibitor that decreases the uptake of methotrexate through inhibiting OAT1 and OAT3.
  • The activation of PKC decreases the transport activity of OATs, it to downregulate OAT1- and rOAT3-mediated organic anion transport across the basolateral membrane of the proximal tubule in a similar manner. This inhibitory effect is also associated with altered substrate selectivity. The reduced OATmediated transport activity is rescued by PKC inhibitors [19].
  • Folic acids: Folic acid and its derivatives may act as activators of certain OATs, which influences folate transport in the body [20].

Alterations of the functionAlterations of the function

The pharmacokinetics and disposal of drugs may be significantly impacted by modifications in the activity of OATs, which can arise from a variety of causes.

Genetic polymorphisms[21]Genetic polymorphisms[21]

Examining the pharmacological effects of naturally occurring mutations in OATs is essential because they may explain different responses to drug treatment. As of right now, investigation has been conducted only into the genetic polymorphisms of OAT1-4.

  • OAT1: numerous SNPs, both intronic and exonic, have been found in individuals representing the main ethno-geographical divisions. Among the results, we can observe cases, such as the R50H variant, where there is an increased uptake of acyclic nucleoside phosphonates, but no changes in the transport of PAH (used as a control in the study of these transporters) are identified; other variants, like K525I, P104L, or R293W, exhibit no change in function; lastly, certain variants, like R454Q, do not exhibit any uptake of PAH, but show normal renal clearance of acyclic nucleoside phosphonates.
  • OAT2: compared to the other three transporters, OAT2 has far fewer SNPs, these being common among individuals of different ethnic groups. However, no major change in function has been identified in any of them.
  • OAT3: the polymorphisms in this transporter that have been investigated primarily indicate changes in the transport of cimetidine and ES, with some variants (like R149S or G239X) showing no uptake at all, and others (like R277W) solely showing reduced ES uptake.
  • OAT4: this transporter's polymorphisms are the most researched. Important variants include the E278K, which has decreased uptake of ES, Dehydroepiandrosterone sulfate, and ochratoxin A (OTA) due to a decrease in maximum transporting rate and transporter-substrate affinity; the L29P, R48X, and H469R variants, which have decreased uptake of ES, OTA, and uric acid; and the T392I variant, whose reduced function is caused by impaired expression of the transporter membrane.

Numerous questions, including what causes this change in function and why the alterations occur, remain unanswered in the study of genetic polymorphisms and their impacts.

Disease states[3]Disease states[3]

Kidney disorders and other diseases can significantly change the expression and activity of OATs, changing their function and ultimately impacting how the body handles different substances.

Acute kidney injury is caused by drug/toxin-induced renal toxicity and renal ischemia, and usually produces a decrease in the glomerular filtration rate and affects secretion and absorption in the renal tubules. Decreased levels of mRNA and protein expression of OAT1 and OAT3 have been observed in patients with this disease, being one of the possible explanations for this that the toxicity is caused by gentamicin, and this antibiotic down-regulates the expression of the transporters, which also contributes to the development of the disease by the reduction in renal function.

Chronic kidney failure produces a gradual decrease in glomerular filtration rate and renal clearance, resulting in the accumulation of various toxins and endogenous substances, leading to renal failure. It is believed that the buildup of toxins and metabolites is what causes the mRNA and protein expression of OAT1 and OAT3 to decline in people with this illness, inhibiting, in addition, the transport produced by the OATs.

In addition to renal diseases, alterations in OATs have been observed in patients with diabetes and cholestasis, observing a reduction in mRNA and protein expression levels of OAT1, OAT2 and OAT3 in the first condition. Cholestasis is a liver disease in which the flow of bile from the liver is reduced or obstructed, and reduced levels of protein expression of OAT1 and OAT3 have been observed.

These findings show that, in order to effectively treat patients with any of these diseases, drug dosages must be modified while accounting for the glomerular filtration rate and OAT expression.

Sex factorSex factor

Differences in mRNA and protein expression of OAT1, OAT2 and OAT3 have been identified between female and male mice, suggesting the possible regulatory role of sex hormones[14]. Research has revealed that male mice's kidneys express more OAT1 and OAT3 than those of female mice, which may be a sign of androgen stimulation and estrogen inhibition. On the other hand, OAT2 expression has been found to be higher in females than in males, suggesting that androgen inhibition and estrogen and progesterone stimulation may be occurring[22].

Despite these results, research is still ongoing to determine the reasons for the reported variations in OAT expression between the sexes as well as why these inhibitions and stimulations occur.

Organic anion transporter and organic cation transporter 3D structuresOrganic anion transporter and organic cation transporter 3D structures

Organic anion transporter 3D structures

AuthorsAuthors

Laura Fernández Rosa, Blanca Rosas Pérez & Vera Ruiz Montés

ReferencesReferences

  1. ↑ 1.0 1.1 1.2 1.3 1.4 Nigám, S. K., Bush, K. T., Gleb Martovetsky, Sun Young Ahn, Liu, H. C., Richard, E., Bhatnagar, V., & Wu, W. (2015). The Organic Anion Transporter (OAT) Family: A Systems Biology Perspective. Physiological Reviews, 95(1), 83–123. https://doi.org/10.1152/physrev.00025.2013
  2. ↑ Mor, A. L., Kaminski, T. W., Karbowska, M., & Pawlak, D. (2018). New insight into organic anion transporters from the perspective of potentially important interactions and drugs toxicity. Journal of Physiology and Pharmacology, 69(3)
  3. ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 Zhang, J., Wang, H., Fan, Y., Yu, Z., & You, G. (2021). Regulation of organic anion transporters: Role in physiology, pathophysiology, and drug elimination. Pharmacology & therapeutics, 217, 107647. https://doi.org/10.1016/j.pharmthera.2020.107647
  4. ↑ 4.0 4.1 4.2 Koepsell, H. (2013). The SLC22 family with transporters of organic cations, anions and zwitterions. Molecular aspects of medicine, 34(2-3), 413-435. https://doi.org/10.1016/j.mam.2012.10.010
  5. ↑ UniProt. (2023). Uniprot.org. https://www.uniprot.org/uniprotkb/Q4U2R8/entry
  6. ↑ UniProt. (2023). Uniprot.org. https://www.uniprot.org/uniprotkb/Q9Y694/entry
  7. ↑ UniProt. (2023). Uniprot.org. https://www.uniprot.org/uniprotkb/Q8TCC7/entry
  8. ↑ UniProt. (2023). Uniprot.org. https://www.uniprot.org/uniprotkb/Q9NSA0/entry
  9. ↑ Burckhardt, G., Burckhardt, B.C. (2011). In Vitro and In Vivo Evidence of the Importance of Organic Anion Transporters (OATs) in Drug Therapy. In: Fromm, M., Kim, R. (eds) Drug Transporters. Handbook of Experimental Pharmacology, vol 201. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-14541-4_2
  10. ↑ 10.0 10.1 Roth, M., Obaidat, A. and Hagenbuch, B. (2012), OATPs, OATs and OCTs: the organic anion and cation transporters of the SLCO and SLC22A gene superfamilies. British Journal of Pharmacology, 165: 1260-1287. https://doi.org/10.1111/j.1476-5381.2011.01724.x
  11. ↑ 11.0 11.1 11.2 11.3 Tsigelny, I.F., Kovalskyy, D., Kouznetsova, V.L. et al. Conformational Changes of the Multispecific Transporter Organic Anion Transporter 1 (OAT1/SLC22A6) Suggests a Molecular Mechanism for Initial Stages of Drug and Metabolite Transport. Cell Biochem Biophys 61, 251–259 (2011). https://doi.org/10.1007/s12013-011-9191-7
  12. ↑ 12.0 12.1 Drew, D., North, R. A., Kumar Nagarathinam, & Tanabe, M. (2021). Structures and General Transport Mechanisms by the Major Facilitator Superfamily (MFS). Chemical Reviews, 121(9), 5289–5335. https://doi.org/10.1021/acs.chemrev.0c00983
  13. ↑ 13.0 13.1 Pizzagalli, M. D., Bensimon, A., & Giulio Superti‐Furga. (2020). A guide to plasma membrane solute carrier proteins. The FEBS Journal, 288(9), 2784–2835. https://doi.org/10.1111/febs.15531
  14. ↑ 14.0 14.1 Anzai, N., Kanai, Y., & Endou, H. (2006). Organic anion transporter family: current knowledge. Journal of pharmacological sciences, 100(5), 411-426. https://doi.org/10.1254/jphs.CRJ06006X
  15. ↑ Murray, M. T., & Zhou, F. (2017). Trafficking and other regulatory mechanisms for organic anion transporting polypeptides and organic anion transporters that modulate cellular drug and xenobiotic influx and that are dysregulated in disease. British Journal of Pharmacology, 174(13), 1908–1924. https://doi.org/10.1111/bph.13785
  16. ↑ Granados, J. C., Bhatnagar, V., & Nigám, S. K. (2022). Blockade of Organic Anion Transport in Humans After Treatment With the Drug Probenecid Leads to Major Metabolic Alterations in Plasma and Urine. Clinical Pharmacology & Therapeutics, 112(3), 653–664. https://doi.org/10.1002/cpt.2630
  17. ↑ 17.0 17.1 Inotsume, N., Nishimura, M., Nakano, M., Fujiyama, S., & Sato, T. (1990). The inhibitory effect of probenecid on renal excretion of famotidine in young, healthy volunteers. The Journal of Clinical Pharmacology, 30(1), 50-56. https://doi.org/10.1002/j.1552-4604.1990.tb03438.x Cite error: Invalid <ref> tag; name "prob" defined multiple times with different content
  18. ↑ Dehkhoda, S., Bagheri, M., Heydari, M., & Rabieh, S. (2022). Extraction of carboxylated nanocellulose from oat husk: Characterization, surface modification and in vitro evaluation of indomethacin drug release. International Journal of Biological Macromolecules, 212, 165-171
  19. ↑ Takeda, M., Sekine, T., & Endou, H. (2000). Regulation by protein kinase C of organic anion transport driven by rat organic anion transporter 3 (rOAT3). Life sciences, 67(9), 1087-1093. https://doi.org/10.1016/S0024-3205(00)00694-9
  20. ↑ Takeuchi, A., Masuda, S., Saito, H., Hashimoto, Y., & Inui, K. I. (2000). Trans-stimulation effects of folic acid derivatives on methotrexate transport by rat renal organic anion transporter, OAT-K1. Journal of Pharmacology and Experimental Therapeutics, 293(3), 1034-1039
  21. ↑ Li, Z., Lam, P., Zhu, L., Wang, K., & Zhou, F. (2012). Current Updates in the Genetic Polymorphisms of Human Organic Anion Transporters (OATs). Journal of Pharmacogenomics and Pharmacoproteomics, 3, 1-8. https://doi.org/10.4172/2153-0645.1000E127
  22. ↑ Ljubojevic, M., Balen, D., Breljak, D., Kusan, M., Anzai, N., Bahn, A., ... & Sabolic, I. (2007). Renal expression of organic anion transporter OAT2 in rats and mice is regulated by sex hormones. American Journal of Physiology-Renal Physiology, 292(1), F361-F372. https://doi.org/10.1152/ajprenal.00207.2006

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