Unique metabolite preferences of the drug transporters OAT1 and OAT3 analyzed by machine learning

Anisha K Nigam,Julia G Li,Kaustubh Lall,Da Shi,Kevin T Bush,Vibha Bhatnagar,Ruben Abagyan,Sanjay K Nigam

doi:10.1074/jbc.ra119.010729

Anisha K Nigam, Julia G Li + Show 6 more

Open Access

https://doi.org/10.1074/jbc.ra119.010729

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Abstract

The multispecific organic anion transporters, OAT1 (SLC22A6) and OAT3 (SLC22A8), the main kidney elimination pathways for many common drugs, are often considered to have largely-redundant roles. However, whereas examination of metabolomics data from Oat-knockout mice (Oat1 and Oat3KO) revealed considerable overlap, over a hundred metabolites were increased in the plasma of one or the other of these knockout mice. Many of these relatively unique metabolites are components of distinct biochemical and signaling pathways, including those involving amino acids, lipids, bile acids, and uremic toxins. Cheminformatics, together with a "logical" statistical and machine learning-based approach, identified a number of molecular features distinguishing these unique endogenous substrates. Compared with OAT1, OAT3 tends to interact with more complex substrates possessing more rings and chiral centers. An independent "brute force" approach, analyzing all possible combinations of molecular features, supported the logical approach. Together, the results suggest the potential molecular basis by which OAT1 and OAT3 modulate distinct metabolic and signaling pathways in vivo As suggested by the Remote Sensing and Signaling Theory, the analysis provides a potential mechanism by which "multispecific" kidney proximal tubule transporters exert distinct physiological effects. Furthermore, a strong metabolite-based machine-learning classifier was able to successfully predict unique OAT1 versus OAT3 drugs; this suggests the feasibility of drug design based on knockout metabolomics of drug transporters. The approach can be applied to other SLC and ATP-binding cassette drug transporters to define their nonredundant physiological roles and for analyzing the potential impact of drug-metabolite interactions.

Highlights

The multispecific organic anion transporters, OAT1 (SLC22A6) and OAT3 (SLC22A8), the main kidney elimination pathways for many common drugs, are often considered to have largelyredundant roles
The goal of this study was to identify the molecular features/ characteristics determining ligand–substrate interaction with either OAT1 or OAT3; we focused our attention on those metabolites that accumulate in the plasma of one of the knockouts but not the other
Ϳ8% of the unique OAT1 metabolites were found to be components of the pathway involved in the metabolism of ␥-glutamyl amino acids, whereas the metabolism of the primary and secondary bile acids comprises a substantial fraction of the OAT3-unique metabolites (Fig. S1)

Summary

Introduction

The multispecific organic anion transporters, OAT1 (SLC22A6) and OAT3 (SLC22A8), the main kidney elimination pathways for many common drugs, are often considered to have largelyredundant roles. SLC22 transporters are highly conserved across organisms (including humans) and, along with other multi-, oligo-, and mono-specific SLC and ATPbinding cassette (ABC) transporters, function collectively as an integrated network of influx and efflux transporters involved in metabolism, signaling, and other aspects of physiological homeostasis (8 –12). Consistent with this notion, SLC22 transporters are expressed in many tissues and have the ability to interact with a diverse range of endogenous and exogenous molecules [13,14,15,16]. OAT1 and OAT3 are generally considered the main organic anion “drug” transporters in the kidney, as well as other tissues (6, 7, 18 –20), their physiological role in transporting endogenous metabolites [21,22,23,24,25] and in mediating inter-organ crosstalk (the “Remote Sensing and Signaling Theory”) is rapidly becoming apparent (5, 9, 26 –31)

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