Organic Anion Transporters of the SLC22 Family: Biopharmaceutical, Physiological, and Pathological Roles

Abstract

The human organic anion transporters OAT1, OAT2, OAT3, OAT4 and URAT1 belong to a family of poly-specific transporters mainly located in kidneys. Selected OATs occur also in liver, placenta, and brain. OATs interact with endogenous metabolic end products such as urate and acidic neutrotransmitter metabolites, as well as with a multitude of widely used drugs, including antibiotics, antihypertensives, antivirals, anti-inflammatory drugs, diuretics and uricosurics. Thereby, OATs play an important role in renal drug elimination and have an impact on pharmacokinetics. In this review we focus on the interaction of human OATs with drugs. We report the affinities of human OATs for drug classes and compare the putative importance of individual OATs for renal drug excretion. The role of OATs as sites of drug-drug interaction and mediators cell toxicity, their gender-dependent regulation in health and diseased states, and the possible impact of single nucleotide polymorphisms are also dealt with.

Identification of a New Urate and High Affinity Nicotinate Transporter, hOAT10 (SLC22A13)

“…Among these are metabolites as well as exogenous substances such as drugs and environmental toxins, which are substrates for transporters of a family called solute carrier (SLC) 2 family 22A. This transporter family consists of organic anion transporters (OATs), organic cation transporters (OCTs), and zwitterion transporters.…”

“…2 The abbreviations used are: SLC, solute carrier; OAT, organic anion transporter; OCT, organic cation transporter; PAH, p-aminohippurate; CCD, cortical collecting duct; SMCT1, sodium-coupled monocarboxylate transporter; URAT1, urate transporter 1; PBS, phosphate-buffered saline; RT, reverse transcription; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; BBMV, brush border membrane vesicle; BLMV, basolateral membrane vesicle; HCTZ, hydrochlorothiazide; ES, estrone sulfate. cDNA Clone-Sequencing of the entire expressed sequence tag clone, which we purchased from the Resource Center/Primary Data Base, cloned into pSPORT6 expression vector (IMAGp998D1711455Q3; GenBank TM accession number BI517655), using an automated sequencer (Applied Biosystems, Inc., Weiterstadt, Germany) and on-line services (e.g.…”

The Large Extracellular Loop of Organic Cation Transporter 1 Influences Substrate Affinity and Is Pivotal for Oligomerization

“…rOct1 chimera containing the EL of rOat1 (rOct1(rOat1-l)) showed oligomerization but reduced transporter amount in the plasma membrane. For rOct1(6⌬C-l) and rOct1(rOat1- Polyspecific organic cation transporters (OCTs) 2 and organic anion transporters (OATs) of the SLC22 transporter family play a pivotal role in absorption, excretion, and tissue distribution of drugs and various endogenous compounds, such as neurotransmitters and prostaglandins (1,2). Polymorphisms in OCTs influence the therapeutic effect during treatment of diabetes with metformin and nephrotoxic side effects during treatment of cancer with cisplatin (3).…”

“…Polymorphisms in OCTs influence the therapeutic effect during treatment of diabetes with metformin and nephrotoxic side effects during treatment of cancer with cisplatin (3). Following the first identifications of rat Oct1 (rOct1) (4) and rat Oat1 (rOat1) (5), functional properties of OCTs and OATs have been studied in detail, and effects of mutations on transport functions have been investigated (1,2). OCTs and OATs contain 12 transmembrane ␣-helices (TMHs), intracellular N and C termini, a large extracellular loop between TMH1 and TMH2, and a large intracellular loop between TMH6 and TMH7.…”

“…OCTs and OATs contain 12 transmembrane ␣-helices (TMHs), intracellular N and C termini, a large extracellular loop between TMH1 and TMH2, and a large intracellular loop between TMH6 and TMH7. Data were obtained that indicate that transporter functions can be regulated by phosphorylation (2,6). Employing structural models derived from the crystal structures of bacterial transporters of the same superfamily, the major solute facilitator superfamily, mutagenesis attempts have been made to map the substrate binding regions of OCTs and OATs (7)(8)(9).…”