Abstract
Genes central to drug absorption, distribution, metabolism and elimination (ADME) also regulate numerous endogenous molecules. The Remote Sensing and Signaling Hypothesis argues that an ADME gene-centered network—including SLC and ABC “drug” transporters, “drug” metabolizing enzymes (DMEs), and regulatory genes—is essential for inter-organ communication via metabolites, signaling molecules, antioxidants, gut microbiome products, uremic solutes, and uremic toxins. By cross-tissue co-expression network analysis, the gut, liver, and kidney (GLK) formed highly connected tissue-specific clusters of SLC transporters, ABC transporters, and DMEs. SLC22, SLC25 and SLC35 families were network hubs, having more inter-organ and intra-organ connections than other families. Analysis of the GLK network revealed key physiological pathways (e.g., involving bile acids and uric acid). A search for additional genes interacting with the network identified HNF4α, HNF1α, and PXR. Knockout gene expression data confirmed ~60–70% of predictions of ADME gene regulation by these transcription factors. Using the GLK network and known ADME genes, we built a tentative gut-liver-kidney “remote sensing and signaling network” consisting of SLC and ABC transporters, as well as DMEs and regulatory proteins. Together with protein-protein interactions to prioritize likely functional connections, this network suggests how multi-specificity combines with oligo-specificity and mono-specificity to regulate homeostasis of numerous endogenous small molecules.
Highlights
As examples, the transporters OAT1 (SLC22A6) and OAT3 (SLC22A8) are perhaps the major multi-specific transporters of small molecule organic anionic drugs handled by the kidney[6,7]
In a recent analysis of the organic anion transporter, OAT3 (SLC22A8), it was found that this “drug” transporter functions in the movement of endogenous metabolites flowing through the “gut-liver-kidney” axis[10]
Using available tissue-specific knockout transcriptomics data and our own ChIP-seq data, we were able to substantially validate key regulatory pathways implicated in our analyses. It has been possible, after decades of physiological studies, to connect SLC and ABC transporters, along with certain drug metabolizing enzymes (DMEs), in the same or different tissues for a limited number of metabolites[2,3], it has been difficult to define such relationships given the discovery of hundreds of transporters and enzymes, many for which the specific function remains unclear, with sometimes unusual patterns of tissue expression
Summary
The transporters OAT1 (SLC22A6) and OAT3 (SLC22A8) are perhaps the major multi-specific transporters of small molecule organic anionic drugs handled by the kidney[6,7]. That many of the OAT-transported metabolites (e.g., tryptophan derivatives transported across the gut, bile acids, uremic solutes and uremic toxins of chronic kidney disease) are modified by phase I and phase II DMEs (e.g., sulfation, glucuronidation) before being transported by the kidney suggests intimate connections between transporters and DMEs in the gut, liver and kidney These and other drug transporter genes, as well as closely related genes, may play essential roles in small molecule inter-organ communication. The broader theory of how inter-organ and inter-organismal small organic molecule communication (e.g., metabolites, signaling molecules, antioxidants) is regulated by SLC and ABC transporters--differentially expressed in various remotely interacting organs and organisms--has been termed the “Remote Sensing and Signaling Hypothesis”[2] This theory is increasingly supported, circumstantially, by the types of metabolomics and transport studies described above[1,17,18,19,20,21,22]
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