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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, the OATs play a role in the cellular uptake, biotransformation, and clearance of the physiological and toxic compounds, many of which are excreted by the kidney. Although much of the original work in the field was based on in vitro data, in recent years a number of studies in Oat knockout mice, as well as analysis of the consequences of human SNPs, have cemented this view. Systems biology approaches applied to knockout mice metabolomics and transcriptomics data suggest a broader role for OATs in metabolism and signaling, including communication occurring between organs. This view is more fully expressed in the Remote Sensing and Signaling Theory, which may be relevant to both SLC and ABC “drug” transporters, as well as drug metabolizing enzymes.

      By understanding the mechanisms of these transporters, it may be possible to predict certain drug–drug interactions [88] and drug–metabolite interactions [88]. Regulation of OATs is a complicated process influenced by multiple intracellular signaling pathways and by various PTMs. Most studies have examined these regulatory factors in isolation. How they work in concert to modulate OAT function, to improve OAT‐related medical treatment, and to keep body homeostasis are important questions that will also provide insights into the workings of the remote sensing and signaling system.

ACKNOWLEDGMENTS

      The authors would like to gratefully acknowledge Drs. Kevin T. Bush, Megha Nagle, David M. Truong, Vibha Bhatnagar, Gregory Kaler, Satish A. Eraly, and Wei Wu for their contributions to previous editions of this chapter. We also wish to thank other members of the Nigam lab who have, over many years, contributed to the material discussed here. Finally, we would like to thank Zhengxuan Liang, from Dr. You’s lab, for her help during the revision process.

REFERENCES