The Molecular Pharmacology of Organic Anion Transporters: from DNA to FDA?

Eraly, Satish A.; Bush, Kevin T.; Sampogna, Rosemary V.; Bhatnagar, Vibha; Nigám, Sanjay K.

doi:10.1124/mol.65.3.479

Cited by 74 publications

(45 citation statements)

References 107 publications

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“…These data may help explain drug-drug interactions (DDIs) but also may explain differences in pharmacokinetics in different patients, some of whom may have transporter single-nucleotide polymorphisms (SNPs) that lead to more rapid or relatively delayed transport. This represents a large body of work by many investigators, and it is impossible to cover each transporter (1,7,21,(23)(24)(25)(26). In this review, however, we focus mainly on OAT1, OAT3, and OCT2, which have emerged as the primary transporters for many common drugs, toxins, and metabolites encountered in the clinical renal setting.…”

Section: Basic Organic Ion Transporter Physiologymentioning

confidence: 99%

Handling of Drugs, Metabolites, and Uremic Toxins by Kidney Proximal Tubule Drug Transporters

Nigám¹,

Wu²,

Bush³

et al. 2015

Clinical Journal of the American Society of Nephrology

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229

192

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The proximal tubule of the kidney plays a crucial role in the renal handling of drugs (e.g., diuretics), uremic toxins (e.g., indoxyl sulfate), environmental toxins (e.g., mercury, aristolochic acid), metabolites (e.g., uric acid), dietary compounds, and signaling molecules. This process is dependent on many multispecific transporters of the solute carrier (SLC) superfamily, including organic anion transporter (OAT) and organic cation transporter (OCT) subfamilies, and the ATP-binding cassette (ABC) superfamily. We review the basic physiology of these SLC and ABC transporters, many of which are often called drug transporters. With an emphasis on OAT1 (SLC22A6), the closely related OAT3 (SLC22A8), and OCT2 (SLC22A2), we explore the implications of recent in vitro, in vivo, and clinical data pertinent to the kidney. The analysis of murine knockouts has revealed a key role for these transporters in the renal handling not only of drugs and toxins but also of gut microbiome products, as well as liverderived phase 1 and phase 2 metabolites, including putative uremic toxins (among other molecules of metabolic and clinical importance). Functional activity of these transporters (and polymorphisms affecting it) plays a key role in drug handling and nephrotoxicity. These transporters may also play a role in remote sensing and signaling, as part of a versatile small molecule communication network operative throughout the body in normal and diseased states, such as AKI and CKD.

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Section: Basic Organic Ion Transporter Physiologymentioning

confidence: 99%

Handling of Drugs, Metabolites, and Uremic Toxins by Kidney Proximal Tubule Drug Transporters

Nigám¹,

Wu²,

Bush³

et al. 2015

Clinical Journal of the American Society of Nephrology

Self Cite

229

192

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“…Since there could conceivably be alternative transporters compensating for the loss of Oat1 or Oat3, we also determined the expression of other transporters implicated in renal organic anion transport, the OA-transporting polypeptides (OATPs; Slco family genes) (12) and the multidrug resistance (MDR)/ ATP-binding cassette (ABC) transporters (Abcc family genes) (30), as well as expression of the OAT-related transporters, the organic cation transporters (OCTs) and organic cation/carnitine transporters (OCTNs) (10). No significant changes Ͼ50% in expression of any of these genes were noted in either Oat1…”

Section: Thus the Fact That Oat3 Expression Is Decreased Approximatelmentioning

confidence: 99%

“…The knowledge of the mechanisms involved in proximal tubular OA secretion has greatly increased in recent years due to cloning of potential OA transporters (OAT) and establishment of their localization in the kidney, as well as to in vitro studies in expression systems (for review, see Refs. 6,9,10,19,27,29,31,42). Little is still known, however, about the functional contribution of the individual transporter for a given substrate in the intact organism.…”

mentioning

confidence: 99%

Overlapping in vitro and in vivo specificities of the organic anion transporters OAT1 and OAT3 for loop and thiazide diuretics

Vallon¹,

Rieg²,

Ahn³

et al. 2008

American Journal of Physiology-Renal Physiology

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117

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“…The analysis of intron phasing suggests that the OAT, OCT, and OCTN lineages of the slc22 family formed after the divergence of vertebrates and invertebrates. Subsequently, these lineages expanded through independent tandem duplications to produce multiple gene pairs (17,18). For human OAT1, four splice variants, i.e., OAT1-1 to OAT1-4, exist, whereas individual roles of these variants are not known (3,23).…”

Section: Genomic Organization and Possible Transcriptional Regulationmentioning

confidence: 99%

Molecular physiology of renal organic anion transporters

Sekine¹,

Miyazaki²,

Endou³

2006

American Journal of Physiology-Renal Physiology

218

167

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Recent advances in molecular biology have identified three organic anion transporter families: the organic anion transporter (OAT) family encoded by SLC22A, the organic anion transporting peptide (OATP) family encoded by SLC21A (SLCO), and the multidrug resistance-associated protein (MRP) family encoded by ABCC. These families play critical roles in the transepithelial transport of organic anions in the kidneys as well as in other tissues such as the liver and brain. Among these families, the OAT family plays the central role in renal organic anion transport. Knowledge of these three families at the molecular level, such as substrate selectivity, tissue distribution, and gene localization, is rapidly increasing. In this review, we will give an overview of molecular information on renal organic anion transporters and describe recent topics such as the regulatory mechanisms and molecular physiology of urate transport. We will also discuss the physiological roles of each organic anion transporter in the light of the transepithelial transport of organic anions in the kidneys.OAT; urate; organic anion transporting peptide; multidrug resistance-associated protein THE ORGANIC ANION (OA) transport system has been a major subject in renal physiology over the past 100 years, because this system represents the tubular secretory pathway. OAs include numerous substances of both endogenous and exogenous origins, and the renal OA transport system plays a pivotal role in the elimination of potentially toxic compounds including metabolites, xenobiotics, and drugs. Because of its complexity, there are still limitations in a detailed analysis of the renal OA transport system by physiological techniques. A notable advance was made in the 1990s by the identification of three major organic anion transporter families: the OAT (organic anion transporter) family encoded by SLC22A, the organic anion transporting peptide (OATP) family encoded by SLCO, and the multidrug resistance-associated protein (MRP) family encoded by ABCC (ATP-binding cassette) superfamily. The identification of each transporter enabled us to perform precise functional analyses of the system. Molecular knowledge in this area has rapidly increased, and various information has appeared within the last few years. In this review, first, we will give an overview of molecular information on OA transporters. Then, we will focus on recent advances, particularly those in the study of the OAT family, which represents the major and classic renal OA transport system. With regard to the OATP and MRP families, we will touch only potentially important points in renal physiology. The major topics described in this paper are as follows: 1) regulatory mechanisms of OA transporters, such as gender differences, intracellular signaling, genomic organization, pathophysiological states and scaffolding proteines; 2) molecular physiology of the renal urate transporter; and 3) organization of transepithelial transport of organic anions. For historical and physiological backgrounds on renal OA...

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The Molecular Pharmacology of Organic Anion Transporters: from DNA to FDA?

Cited by 74 publications

References 107 publications

Handling of Drugs, Metabolites, and Uremic Toxins by Kidney Proximal Tubule Drug Transporters

Handling of Drugs, Metabolites, and Uremic Toxins by Kidney Proximal Tubule Drug Transporters

Overlapping in vitro and in vivo specificities of the organic anion transporters OAT1 and OAT3 for loop and thiazide diuretics

Molecular physiology of renal organic anion transporters

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