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4 ORGANIC ANION TRANSPORTERS (OATs)
Jeffry C. Granados1, Jinghui Zhang2, Guofeng You2, and Sanjay K. Nigam3
1 Department of Bioengineering, University of California, San Diego, CA, USA
2 Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
3 Departments of Pediatrics and Medicine, University of California, San Diego, CA, USA
4.1 OAT FAMILY
4.1.1 Introduction
Organic anion transporters (OATs) belong to the largest family of secondary active membrane transporters: the major facilitator superfamily (MFS), which is conserved from bacteria to mammals [1–3]. MFS transporters function as transmembrane uniporters, symporters, and antiporters, and transport a wide range of hydrophilic and amphiphilic substrates, including inorganic ions (e.g., Na+, Cl–, HCO3 –), endogenous metabolites (e.g., amino acids, sugars, neurotransmitters), signaling molecules (cyclic nucleotides, prostaglandins), and xenobiotics (drugs and toxins). Within this MFS superfamily, the OATs are members of Solute Carrier 22 (SLC22), a family of solute carriers which currently, in humans, consists of over 30 named transporters expressed in most barrier epithelia in mammals, including the kidney, choroid plexus, blood–brain barrier, biliary tract, intestine, retinal–blood barrier, olfactory mucosa, blood–testis barrier, and others [4]. These structurally similar proteins mediate the partitioning of a wide variety of compounds (e.g., endogenous metabolites, signaling molecules, natural products, endogenous toxins, environmental toxins, and drugs) into these various body fluid and tissue compartments, and they have been categorized based on the specific type of substrate which they transport, as well as sequence homology, including the OATs, as well as the organic cation transporters (OCTs), carnitine transporters (OCTNs), unknown solute transporters (USTs), and fly‐like putative transporters (Flipts) [5–12].
Until recently, much of the physiological knowledge concerning OAT function has been found by studying prototypical substrates, such as p‐aminohippurate (PAH) and estrone‐3‐sulfate. The “classical” organic anion (OA) or organic acid secretory system is thought to be fundamentally involved in the excretion of common drugs, toxins, and endogenous metabolites into the urine, thereby maintaining the equilibrium of anionic metabolites in the body. OATs, the proteins that underlie the OA secretory system, are an example of secondary (and/or tertiary) active membrane transporters, which move substrates across the cell membrane by utilizing a transmembrane electrochemical gradient of the substrate itself or of another solute [13]. To date, over 10 OAT family members have been clearly identified in humans and rodents (Table 4.1). Several orphan family members have been identified as well and are likely to be OATs [6].
Over the past several years, there has been considerable progress in understanding the molecular basis and consequence of OAT‐mediated transport through the utilization of system biology approaches combining large data sets from transcriptomic and metabolomic studies [11]. Furthermore, these transporters have also been found to be present in numerous epithelial barrier tissues other than the kidney, including the olfactory mucosa, liver, choroid plexus, retina, placenta, and circulating blood cells, which potentially implicates OATs more broadly in remote communication processes. Moreover, the completed genome sequencing in several species has uncovered unique features of the