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

Abstract

Quantitative systems pharmacology (QSP) has emerged as a transformative science in drug discovery and development. It is now time to fully rethink the biological functions of drug metabolizing enzymes (DMEs) and transporters within the framework of QSP models. The large set of DME and transporter genes are generally considered from the perspective of the absorption, distribution, metabolism, and excretion (ADME) of drugs. However, there is a growing amount of data on the endogenous physiology of DMEs and transporters. Recent studies-including systems biology analyses of "omics" data as well as metabolomics studies-indicate that these enzymes and transporters, which are often among the most highly expressed genes in tissues like liver, kidney, and intestine, have coordinated roles in fundamental biological processes. Multispecific DMEs and transporters work together with oligospecific and monospecific ADME proteins in a large multiorgan remote sensing and signaling network. We use the Remote Sensing and Signaling Theory (RSST) to examine the roles of DMEs and transporters in intratissue, interorgan, and interorganismal communication via metabolites and signaling molecules. This RSST-based view is applicable to bile acids, uric acid, eicosanoids, fatty acids, uremic toxins, and gut microbiome products, among other small organic molecules of physiological interest. Rooting this broader perspective of DMEs and transporters within QSP may facilitate an improved understanding of fundamental biology, physiologically based pharmacokinetics, and the prediction of drug toxicities based upon the interplay of these ADME proteins with key pathways in metabolism and signaling. The RSST-based view should also enable more tailored pharmacotherapy in the setting of kidney disease, liver disease, metabolic syndrome, and diabetes. We further discuss the pharmaceutical and regulatory implications of this revised view through the lens of systems physiology.

Figure 1

Transporter‐mediated clearance of organic anions in the kidney occurs in the proximal tubule and involves both SLC and ABC "drug" transporters. Illustration of the movement of organic anions out of the blood and into the tubular lumen occurring in cells of the proximal tubule. (a) Cross section through an adult kidney. (b) Enlarged area of renal cortex (indicated by dashed box in a) showing a partial nephron, including the glomerulus, proximal convoluted tubule, and a portion of the descending loop of Henle. (c) Enlarged cross section of the proximal tubule (indicated by dashed box in b), showing the arrangement of the epithelial cells around the tubular lumen. (d) Enlarged view of dashed box in c, showing a proximal tubule cell and the arrangement of SLC (OAT1, OAT3) and ABC (MRP2, MRP4) drug transporters. Organic anions (OAs) are moved from the blood and into the cell via SLC transporters (e.g., OAT1, OAT3) found on the basolateral membrane. These small anionic compounds are ultimately effluxed into the urine via ABC transporters (e.g., MRP2 and MRP4) found on the apical membrane. (e, f) Diagrams of the 12 transmembrane domain structure of the SLC e and ABC f drug transporters). [Colour figure can be viewed at wileyonlinelibrary.com]

Figure 2

Remote sensing and signaling via ABC and SLC drug transporters and phase I and phase II drug metabolizing enzymes (DMEs). (a) Schematic representation of how SLC and ABC “multispecific drug” transporters and DMEs (expressed in many tissues) (b) are linked to form a small molecule communication system. A "remote sensing and signaling network" (RSSN)—consisting of multispecific transporters and DMEs functioning together with oligospecific and monospecific counterparts as well as regulatory proteins—helps modulate levels of many thousands of metabolites in tissues and fluids throughout the body. ¹⁹  This remote sensing and signaling system works in parallel with other regulatory systems to maintain homeostasis and has a complex organization and emergent properties, particularly after perturbation. (b) “Drug” transporters consist of SLC and ABC transporters expressed in all epithelial, as well as many nonepithelial, tissues throughout the body. The remote sensing and signaling theory not only emphasizes interorgan communication (red arrows) but also interorganismal communication (blue arrows), such as the movement of small molecules across the intestine (host‐gut microbiome), and/or into breast milk (mother—nursing infant), or across the placental barrier (mother–baby). CNS, central nervous system (adapted from reference 16). [Colour figure can be viewed at wileyonlinelibrary.com]

Figure 3

Interplay of bile acids with transporters, metabolizing enzymes, and the microbiome in the liver, intestine, and kidney. (a) In hepatocytes, bile acids control their own biosynthesis through negative feedback on CYP7A1 and CYP27A1. Cholesterol‐derived bile acids are negatively charged at physiologic pH and require carrier‐mediated transport to cross membranes. Blood to bile transport is governed by Na + taurocholate cotransporting peptide (NTCP), OATP1A2, OATP1B1, and OATP1B3. Secretion of bile acids from the liver into the bile canaliculi occurs primarily by BSEP and MRP2 to a lesser extent. MRP3, MPR4, and OSTα‐OSTβ play a compensatory role in bile acid efflux under cholestatic conditions. (b) Following the delivery of bile acids to the intestinal lumen through the bile ducts, bile acids are actively transported across the apical intestinal brush border membrane by ASBT, followed by efflux across the basolateral membrane and into the portal circulation by OSTα‐OSTβ. Additionally, bile acids in the gut lumen interact with intestinal microbes. Bile acids have direct antimicrobial effects on gut microbes. Conversely, deconjugation of bile acids by gut microbes prevents ASBT‐directed intestinal reuptake. (c) Bile acids are reclaimed in the kidney by active reabsorption in the proximal tubules. The transport mechanisms involved in renal tubular reabsorption involve ASBT and OSTα‐OSTβ expressed on the apical and basolateral membranes, respectively, while OAT3 contributes to secretion. Throughout these pathways, bile acids act as signaling molecules as ligands for G protein–coupled receptors and nuclear receptors. [Colour figure can be viewed at wileyonlinelibrary.com]

Figure 4

Prostaglandin biosynthesis and transport. Illustration of the synthesis of bioactive eicosanoids including prostaglandin E2 (PGE2), epoxyeicosatrienoic acids (EETs), and hydroxyeicosatetraenoic acids (HETEs). These arachidonic acid metabolites are generated principally by cyclooxygenase (COX), lipooxygenase (LOX), and CYP450 enzymes (CYP2C, CYP4A, and CYP4F isoforms). HETEs and EETs have vasoconstrictive and vasodilatory effects, respectively, in blood vessels and the kidney, and phase II metabolism via glucuronidation (including UGT2B7 and UGT1A9) plays a role in bioinactivation, limiting the availability of these compounds for cellular processes. Transporters, including "drug" transporters like OAT3, regulate intratissue and intracellular uptake and efflux of various eicosanoids in the brain and elsewhere. [Colour figure can be viewed at wileyonlinelibrary.com]