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    How organs sense circulating metabolites is a key question. Here, we show that the multi-specific organic anion transporters of drugs, OAT1 (SLC22A6 or NKT) and OAT3 (SLC22A8), play a role in organ sensing. Metabolomics analyses of the serum of Oat1 and Oat3 knockout mice revealed changes in tryptophan derivatives involved in metabolism and signaling. Direct interaction with the transporters was supported with cell-based transport assays. To assess the impact of the loss of OAT1 or OAT3 function on the kidney, an organ where these uptake transporters are highly expressed, knockout transcriptomic data were mapped onto a "metabolic task"-based computational model that evaluates over 150 cellular functions. Despite the changes of tryptophan metabolites in both knockouts, only in the Oat1 knockout were multiple tryptophan-related cellular functions increased. Thus, deprived of the ability to take up kynurenine, kynurenate, anthranilate, and N-formylanthranilate through OAT1, the kidney responds by activating its own tryptophan-related biosynthetic pathways. The results support the Remote Sensing and Signaling Theory, which describes how "drug" transporters help optimize levels of metabolites and signaling molecules by facilitating organ crosstalk. Since OAT1 and OAT3 are inhibited by many drugs, the data implies potential for drug-metabolite interactions (DMI). Indeed, treatment of humans with probenecid, an OAT-inhibitor used to treat gout, elevated circulating tryptophan metabolites. Furthermore, given that regulatory agencies have recommended drugs be tested for OAT1 and OAT3 binding or transport, it follows these metabolites can be used as endogenous biomarkers to determine if drug candidates interact with OAT1 and/or OAT3. Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.


    Jeffry C Granados, Anne Richelle, Jahir M Gutierrez, Patrick Zhang, Xinlian Zhang, Vibha Bhatnagar, Nathan E Lewis, Sanjay K Nigam. Coordinate regulation of systemic and kidney tryptophan metabolism by the drug transporters OAT1 and OAT3. The Journal of biological chemistry. 2021 Mar 21:100575

    PMID: 33757768

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