An Organic Anion Transporter 1 (OAT1)-centered Metabolic Network

Abstract

There has been a recent interest in the broader physiological importance of multispecific "drug" transporters of the SLC and ABC transporter families. Here, a novel multi-tiered systems biology approach was used to predict metabolites and signaling molecules potentially affected by the in vivo deletion of organic anion transporter 1 (Oat1, Slc22a6, originally NKT), a major kidney-expressed drug transporter. Validation of some predictions in wetlab assays, together with re-evaluation of existing transport and knock-out metabolomics data, generated an experimentally validated, confidence ranked set of OAT1-interacting endogenous compounds enabling construction of an "OAT1-centered metabolic interaction network." Pathway and enrichment analysis indicated an important role for OAT1 in metabolism involving: the TCA cycle, tryptophan and other amino acids, fatty acids, prostaglandins, cyclic nucleotides, odorants, polyamines, and vitamins. The partly validated reconstructed network is also consistent with a major role for OAT1 in modulating metabolic and signaling pathways involving uric acid, gut microbiome products, and socalled uremic toxins accumulating in chronic kidney disease. Together, the findings are compatible with the hypothesized role of drug transporters in remote inter-organ and inter-organismal communication: The Remote Sensing and Signaling Hypothesis (Nigam, S. K. (2015) Nat. Rev. Drug Disc. 14, 29). The fact that OAT1 can affect many systemic biological pathways suggests that drug-metabolite interactions need to be considered beyond simple competition for the drug transporter itself and may explain aspects of drug-induced metabolic syndrome. Our approach should provide novel mechanistic insights into the role of OAT1 and other drug transporters implicated in metabolic diseases like gout, diabetes, and chronic kidney disease.A great deal of recent evidence suggests that solute carriers (SLC) 2 play a much broader role in physiology, including signaling and metabolism, than has been previously appreciated (1, 2). Indeed, there has been a recent call for more systematic analysis of the roles of SLCs in metabolism and signaling (1). Perhaps due to heavy emphasis on their key role in pharmacokinetics, members of the SLC (and ABC as well) "drug" transporter families are not generally depicted in biochemical pathways involving the endogenous metabolites they transport (2). Such an omission could have clinical consequences, because drugs directly or indirectly affect pathways normally involved in the movement of key metabolites, pathway intermediates, and signaling molecules, thereby fundamentally affecting cell and organ physiology in normal, pathophysiological, and developmental situations (1, 2). According to the remote sensing and signaling hypothesis, SLC and ABC drug transporters are important in regulating the movement of small endogenous molecules such as key metabolites (e.g. ␣-ketoglutarate, tryptophan metabolites), signaling molecules (e.g. cAMP, prostaglandins, polyamines), vitamins, antioxidant...

Key Role for the Organic Anion Transporters, OAT1 and OAT3, in the in vivo Handling of Uremic Toxins and Solutes

“…This general view is also supported by metabolic reconstructions of “omics” data from the Oat1KO and Oat3KO mice 11, 30, 49 , where it has been demonstrated that Oats regulate biochemical pathways of interorgan and interorganismal communication such as those involving gut microbiome metabolites, energy metabolism, purine metabolism, antioxidants and lipid metabolism and many other pathways altered in CKD. Taken together, this suggests that uremia is in part a disease of disordered remote sensing and signaling 5, 8, 9, 11, 45–47 .…”

The Systems Biology of Drug Metabolizing Enzymes and Transporters: Relevance to Quantitative Systems Pharmacology

“…For example, if an investigational drug is identified as an inhibitor of the drug transporter organic anion transporter 1 (OAT1, SLC22A6), one might consider not only the impact on a co‐administered OAT1 drug substrate, or a single measurable metabolite known to be transported by OAT1, but also the indirect disruption of metabolic as well as sensing and signaling pathways that are facilitated through this transporter (e.g., purine metabolism, short chain fatty acids, gut microbiome products, or tricarboxylic acid (TCA) cycle intermediates) 21,22 …”

“…OAT1 and OAT3 are two of the seven “drug” transporters initially highlighted by the FDA for focus on potential DDIs 25 . Although in vitro , murine knockout, and human studies clearly support their roles in the transport of drugs and toxins, 8,11,17,26,27 recent knockout mouse metabolomics and other studies have clarified the wide range of in vivo endogenous metabolites and signaling molecules capable of interacting with OATs 15,21‐22,28‐30 . The OATs and OAT‐like transporters constitute roughly half the of the SLC22 transporter family, which has over 30 members in humans and/or rodents, relatives of which can even be found in many invertebrates 31 .…”

Gut-derived uremic toxin handling in vivo requires OAT-mediated tubular secretion in chronic kidney disease

“…pounds from the blood and into the cell. Such compounds include a wide array of commonly prescribed drugs, endogenous metabolites, signaling molecules, and toxins (15)(16)(17)(18)(19)(20)(21)(22)(23)(24).…”