accumulation of the antiviral drug oseltamivir [186], and dehydroepiandrosterone sulfate [187], while ex vivo studies of isolated choroid plexus from Oat3 knockout animals showed reduced accumulation of organic anions, including antivirals [4, 126]. Similarly, the placenta protects the fetus from exposure to toxic substrates and allows the delivery of pharmaceutical drugs (such as zidovudine prophylaxis against HIV) by similar mechanisms [188]. OAT4, for example, has been localized to the placenta and is known to transport many drugs such as zidovudine, antibiotics and anti‐hypertensives [189]. The discovery of the olfactory Oat, Oat6, also raises the possibility that SNPs in this gene could be important in determining the efficacy of nasally administered drugs [45, 190].
4.5.6 Remote Sensing and Signaling Theory
Based on knockout metabolomics data and the growing amount of in vitro data indicating that Oats and other Slc and Abc transporters have reasonable or relatively high affinities for signaling molecules (e.g., odorants, cyclic nucleotides, prostaglandins), it has been postulated that they play a key role in the regulation of levels of signaling molecules in cellular, tissue, and body fluid compartments (Fig. 4.3) [45, 48, 51, 62]. This idea is further supported by the fact that not only is the expression of some of these transporters relatively tissue‐specific (e.g., OAT4 in placenta, Oat6 in olfactory mucosa) but also some Oats also have high selectivity for these types of signaling molecules: Oat2 for cGMP, Oat6 for odorants, OAT4 for sex steroid conjugates, Urat1 (originally Rst) for the antioxidant uric acid [45, 48, 51, 62].
These transporters are also clearly involved in the movement of other key metabolites and nutrients, including α‐ketoglutarate, vitamins, flavonoids, and gut microbiome products [120] across tissue barriers (“remote communication”). Moreover, they have been found to regulate central metabolic pathways directly or indirectly [37], and they can also modulate signaling pathways—for example, flavonoids affect MAPK/PI3K signaling [191] and kynurenine, which accumulates in the Oat1 knockout can activate G‐protein‐coupled receptor (GPCR) signaling [192].
FIGURE 4.3 ABC and SLC transporters contribute to remote sensing and signaling. Transporters, including OATs, contribute to inter‐organ and inter‐organismal communication through expression in key organs and shared substrate specificity. This transporter system works in parallel with other established systems to return the body to homeostasis following perturbation.
With permission from Ref. 3.
Other metabolites, such as indole, are produced by the gut bacteria, absorbed by the intestine, then sulfated by liver drug metabolizing enzymes (DMEs). The product, indoxyl sulfate, an OAT substrate, can be toxic—for instance, in the setting of the uremia of CKD. Thus, OAT transport is linked to DME (Phase I and Phase II enzymes in the liver). In this regard, it is worth noting that OAT3 binds glucuronidated compounds (apart from drugs) with reasonable affinity and may be the main pathway by which these Phase II conjugated compounds are eliminated by the kidney. It was observed in cultured cells, rat kidneys, and human kidneys [193] that indoxyl sulfate upregulated OAT1 via AhR and EGFR signaling under the control of miR‐223, and the upregulation on OAT1 was thought to react to the elevated indoxyl sulfate level and to maintain homeostasis through inducing renal secretion. Together the data was interpreted as an example of remote sensing and signaling. Finally, it is clear that growth factors and hormones directly or indirectly modulate the OAT pathway [194]. For example, Oat3 expression and transport activity were impaired in the streptozotocin‐induced type 1 diabetic rats compared with those in wild‐type rats. Streptozotocin was used to damage insulin‐producing beta cells in the pancreas to induce diabetes in animal models, and insulin treatment abolished the effects by streptozotocin [195].
All this has led to the proposal of the “Remote Sensing and Signaling Theory” for SLC and ABC so‐called “drug transporters” [3, 10, 11, 45, 48, 51, 62]. It is a “systems biology” perspective which argues that, as in the cases cited above, the essential physiological role of OATs and other SLC and ABC transporters is to locally and remotely regulate the levels of key metabolites, nutrients and signaling molecules in different tissues, organs, and body fluid compartments. It is also essential for inter‐organismal communication (e.g., gut microbiome‐host, maternal‐fetal, nursing mother‐neonate, odorants released in the urine via Oats and “sensed” by olfactory Oats in another organism.) According to this view, in mammals, drugs and toxins “hijack” this Remote Sensing and Signaling System, a network of transporters and drug metabolizing enzymes, which interacts with and functions in parallel to the neuroendocrine and growth factor systems in inter‐organ communication [76].
To further explore the potential existence of this network, a cross tissue co‐expression network analysis revealed highly connected clusters of transporters, including OATs in the SLC22 family, in the gut, liver, and kidney [196]. Co‐expression networks are interpreted with the assumption that proteins expressed in similar tissues serve similar functions. When taken with the shared substrate specificity between sets of transporters, it appears multi‐specific, oligo‐specific, and mono‐specific transporters are involved in the regulation of endogenous metabolites.
The Remote Sensing and Signaling Theory mainly focuses on inter‐organ communication mediated by drug transporters and drug metabolizing enzymes. As noted in the sections above, many metabolites serve as signaling molecules that bind to nuclear receptors and trigger transcriptional regulation that impacts the expression of key proteins and thus the levels of the signaling metabolite. In this way, a metabolite can contribute to its uptake, efflux, or degradation by activating genes that act upon it, as in the example of indoxyl sulfate, AHR, and OAT1 [193].
While transcriptional regulation is certainly an important aspect, recent work has highlighted the potential for post‐translational modifications to contribute to remote sensing and signaling. Indeed, the OATs have been shown to respond to small molecule stimuli, such as dexamethasone and AG490, by altering the rates of OAT degradation, recycling to the cell membrane, and transport activity [12]. This understudied aspect of communication between endogenous and xenobiotic molecules, coupled with traditional transcriptional regulation, contribute to a robust Remote Sensing and Signaling system that increases the adaptability of tissue response to external stimuli and ultimately facilitates organ crosstalk and inter‐organismal communication (e.g., gut microbes‐host, mother‐nursing infant).
There is now, at many levels, data to support this view in humans and animal models. For example, as described above alteration in the drug handling capacity in the kidney or liver (e.g., due to CKD or liver impairment) can alter the drug handling capacity in other organs [157, 158]. In addition, it has recently been shown in Drosophila, a genetic knockdown of a single organic anion transporter not only led to changes in the expression of multiple transporters, including at least one other organic anion transporter, it also affected the expression of other organic anion transporters in response to methotrexate [197, 198]. This theory serves as a new way of looking at the systemic physiological importance of the many SLC and ABC “drug transporters” expressed in different body tissues—and a framework for exploring novel roles of OATs and other “drug” transporters [48, 51, 114, 199].
4.6 CONCLUSIONS
The organic anion transporters (OATs) are a subclass of the large SLC22 family of transmembrane proteins, which mediate the transport of a wide variety of endogenous metabolites, signaling molecules, and exogenous compounds including potential cytotoxic drugs and toxins. These transporters are expressed in a range of tissues including brain, retina, placenta, testes, olfactory mucosa, liver, intestine, and kidney. Together with Phase I and Phase II metabolizing enzymes,
