Coordinate regulation of systemic and kidney tryptophan metabolism by the drug transporters OAT1 and OAT3

Jeffry C Granados,Anne Richelle,Jahir M Gutierrez,Patrick Zhang,Xinlian Zhang,Vibha Bhatnagar,Nathan E Lewis,Sanjay K Nigam

doi:10.1016/j.jbc.2021.100575

Jeffry C Granados, Anne Richelle + Show 6 more

Open Access

https://doi.org/10.1016/j.jbc.2021.100575

Copy DOI

Abstract

How organs sense circulating metabolites is a key question. Here, we show that the multispecific 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. Several of these metabolites are derived from the gut microbiome and are implicated as uremic toxins in chronic kidney disease. 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 cross talk. Since OAT1 and OAT3 are inhibited by many drugs, the data implies potential for drug–metabolite interactions. 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 that these metabolites can be used as endogenous biomarkers to determine if drug candidates interact with OAT1 and/or OAT3.

Highlights

The SLC22 gene family (OATs, OCTs, OCTNs) encodes for transporters that participate in the uptake of many unique compounds across several tissues, though much of the research has focused on a handful of members (SLC22A1, SLC22A2, SLC22A6, SLC22A8) that handle many common drugs [20, 21]
We compared data from mice genetically deficient in either Oat1 or Oat3 and their wild-type controls. These data sets have previously been examined from a chemoinformatic perspective [23] and to provide a broad overview of affected pathways [24], but here we place an emphasis on their specific role in the disposition of tryptophan metabolites
Because these two transporters are found in the kidney, we analyzed kidney transcriptomic data using Metabolic Task Analysis, a systems biology method that groups genes according to their coordinated roles in the biosynthesis of a limited set of key metabolite intermediates from diverse metabolite inputs

Summary

Introduction

Published metabolomic analyses of Oat1 KO and Oat3 KO mice suggest physiologically important alterations in the handling of endogenous metabolites and gut microbiome products, including some uremic toxins [34, 35]. Of the 17 metabolites that significantly accumulated in the serum of both the Oat1 KO and Oat3 KO animals, four belonged to the Tryptophan Metabolism Subpathway, indicating that these two transporters have an important shared role in regulation of systemic tryptophan metabolism (Fig. 2). Role of OAT1 and OAT3 in tryptophan metabolism tryptophan metabolites were measured in the serum of both mice, and 12 were significantly altered in at least one group.

Results

Conclusion