picture of the OATs at the molecular, evolutionary, and regulatory level [9, 12, 27].
TABLE 4.1 OAT family members a
| Protein name (gene symbol) | Prototypical substrate(s) | Transport mechanism | Human tissue distribution | Membrane localization | Identified species | Gender difference | Human gene locus |
|---|---|---|---|---|---|---|---|
| OAT1 (SLC22A6) | PAH | OA/DC exchange | Kidney | Basolateral | Human, mouse, rat, pig, flounder, Caenorhabditis elegans | (Rat) M > F | 11q12.3 |
| OAT2 (SLC22A7) | PAH | PAH/anion exchange | Liver, kidney | Basolateral in human | Human, mouse, rat | Species dependent | 6q21.1‐2 |
| OAT3 (SLC22A8) | Estrone‐3‐sulfate | OA/DC exchange | Kidney, brain, testis | Basolateral | Human, mouse, rat, pig, rabbit | (Rat) M > F | 11q12.3 |
| OAT4 (SLC22A11) | Estrone‐3‐sultate | OA/DC exchange | Placenta, kidney, brain | Apical | Human | Unknown | 11q13.1 |
| Oat5 (Slc22a19) | Ochratoxin A | Exchanger | — | Apical | Mouse, rat | Unknown | — |
| Oat6 (Slc22a20) | Estrone‐3‐sulfate | Exchanger | — | Unknown | Mouse, rat | Unknown | 11q13.1b |
| OAT7 (SLC22A9) | Estrone‐3‐sulfate | OA/DC exchange | Liver | Sinusoidal | Human | Unknown | 11q12.3 |
| Rat Oat8 (Slc22a25) | Ochratoxin A | OA/DC exchange | — | Apical | Rat | Unknown | — |
| Mouse Oat9 (Slc22a27) | Carnitine | unknown | — | Apical | Mouse | Unknown | — |
| OAT10 (SLC22A13) | Nicotine | Nicotine/anion exchange | Kidney, brain, colon | Apical | Human, rat | (Rat) F > M | 3p22.2 |
| URAT1 (SLC22A12) | Urate | Urate/anion exchange | Kidney | Apical | Human, mouse | (Mouse) M > F | 11q13.1 |
Abbreviations: OA, organic anion; DC, dicarboxylic acid.
a Information in this Table from references [9, 10,14–26].
b A partial transcript in human.
In what follows, after providing basic information about the OATs and considering their pharmacological and toxicological roles, we place a major emphasis on new data revealing their roles in regulation of endogenous physiology and the intracellular post‐translational modifications that impact their expression and function. We cover their roles in handling of natural products. We then discuss their roles in pathophysiology, particularly in the handling of uremic toxins of chronic kidney disease (CKD). A major organizing principle of the chapter is the role of OATs in “remote sensing and signaling” in the service of inter‐organ cross talk and inter‐organismal communication. We thus discuss the Remote Sensing and Signaling Theory, which applies not only to OATs but other drug transporters discussed throughout this book.
4.1.2 Discovery
The first gene encoding an Oat, the novel liver‐specific transporter (Nlt), was cloned and sequenced from rat liver in 1994 [28], although its functional characterization as an Oat was not confirmed until later—at which time it became the second member of the Oat family to be named (Oat2/Slc22a7) [29]. In 1996, a gene cloned from mouse kidney using a novel degenerative PCR strategy was identified as the novel kidney transporter (Nkt) [30–32]. It was proposed to function as an organic anion or organic cation transporter and subsequently demonstrated to perform both functions, though strongly favoring organic anions. Based on sequence homology to Nlt and Oct1, a new gene family, now called SLC22 and numbering over 30 transporters in mammals, was proposed. Functional analyses of its rat homolog subsequently identified Nkt as the first member of Oat family (Oat1/Slc22a6) [33–35]. Although it transports mainly organic anions, it and other Oats can transport organic cations as well [36–39]. Various homology‐based approaches have been used to identify additional Oat family members. For example, Oat3/Slc22a8 was originally identified in a differential display assay comparing gene expression in wild‐type and mice homozygous for the juvenile cystic kidney mutation [40]. Initially identified as Roct (reduced in osteosclerosis transporter), this transporter was then found to share a high degree of identity with Oat3/Slc22a8 genes cloned from both rat brain and human kidney [41, 42]. Meanwhile database searches for clones with homology to Oat family members led to the identification of Oat4/Slc22a11, expressed in the kidney and placenta [43]. In silico homology‐based analyses resulted in the identification of Oat5/Slc22a19 [44] and Oat6/Slc22a20 [45] (which was found, intriguingly, to be expressed mainly in the olfactory mucosa). Somewhat similar approaches led to the identification of other OATs and other transporters (Table