The metabolism of lipophilic xenobiotics, including drugs and nutrients, involves a coordinated process of biotransformation and transport, ultimately aimed at detoxifying and eliminating potentially harmful compounds. Most of the tissues and organs are well equipped with diverse and various drug metabolism enzymes including Phase I (oxidative) and Phase II (conjugative) metabolizing enzymes as well as Phase III transporters. These proteins are present in abundance either at the basal level or are inducible after xenobiotic exposure. Phase I enzymes consist primarily of the cytochrome P450 (CYP) superfamily of microsomal enzymes, which are found abundantly in the liver, gastrointestinal tract, lung and kidney. The Phase II metabolizing or conjugating enzymes, consist of several gene families including sulfotransferases (SULT), UDP-glucuronosyltransferases (UGT), epoxide hydrolases (EPH) and glutathione S-transferases (GST). Phase III transporters, including P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP) and organic anion transporting polypeptide 2 (OATP2) are expressed in many tissues including liver, intestine, kidney, and brain. P-gp and MRP utilize the energy from the hydrolysis of ATP to substrate transport across the cell membrane, and are called ATP binding cassette (ABC) transporters.

The regulation of gene expression of the Phase I, Phase II enzymes and Phase III transporters drug-met3has an important impact on the metabolism, elimination and drug-drug interactions of many therapeutic agents and affects the ability of the human body to protect itself against exposure of environmental xenobiotics. Specific members of the Nuclear Receptor (NR) superfamily function as master regulators of the adaptive response of an organism to xenobiotics. Some of the important nuclear receptors and the drug metabolism and transport proteins they transcriptionally regulate are shown in Figure 1 (based on references [1,2,3,4]). Ligands for the metabolic nuclear receptors are commonly present in cells in much higher (micromolar) concentrations than ligands for steroid receptors (nanomolar range), such as estrogen receptor (ER) and glucocorticoid receptor (GR), which are mediators of endocrine signaling. Three NRs that have overlapping roles in preventing against xeno- and endo-biotic toxicity are PXR, (pregnane X receptor), CAR (constitutive androstane receptor) and FXR (farnesoid X receptor). PXR is a master regulator of the CYP3A4 gene, important since members of this family of enzymes metabolize a large proportion of all prescription drugs. Regulation of CYP3A4 may cause adverse drug-drug interactions, in which metabolism of one drug is accelerated by the other. Another PXR target gene commonly involved in untoward drug–drug interactions is MDR1. CAR is best known for its role as an inducer of the phenobarbital-responsive CYP2B gene family. In addition to CYP genes, PXR and CAR regulate genes encoding phase II drug-metabolizing enzymes, such as UGT1A. Similar to PXR and CAR, the bile acid receptor FXR regulates expression of CYP3A4, MRP2, and SULT2A1. HNF-α has emerged as one of the key regulators of hepatic transport and metabolism of drugs and bile and bile acids. Included in the genes that are regulated by HNF4α are CYP7A1, 8B1 and 27A1 and the transporter OAT2. The Liver X Receptors, LXRα and β are now recognized to be central regulators of cholesterol increasing Cyp7a1as well as ABCG5 and ABCG8. Peroxisome Proliferator-Activated Receptor α (PPARα) induces members of the CYP4A subfamily of enzymes which a central role in the hydroxylation of fatty acid derivatives and cholesterol metabolism.


The transcriptional regulation of genes involved in drug detoxification is highly complex. The nuclear receptors chiefly responsible for these transcriptional events interact functionally with each other to adjust the expression levels of genes encoding transporter proteins and metabolic enzymes that mediate appropriate responses to endo- and xenobiotic challenges in the cellular environment.


1 Urquhart, B. L., Tirona, R. G. and Kim, R. B. (2007) Nuclear receptors and the regulation of drug-metabolizing enzymes and drug transporters: implications for interindividual variability in response to drugs. J Clin Pharmacol 47, 566-578 2 Handschin, C., Lin, J., Rhee, J., Peyer, A. K., Chin, S., Wu, P. H., Meyer, U. A. and Spiegelman, B. M. (2005) Nutritional regulation of hepatic heme biosynthesis and porphyria through PGC-1alpha. Cell 122, 505-515 3 Xu, C., Li, C. Y. and Kong, A. N. (2005) Induction of phase I, II and III drug metabolism/transport by xenobiotics. Arch Pharm Res 28, 249-268 4 Eloranta, J. J. and Kullak-Ublick, G. A. (2005) Coordinate transcriptional regulation of bile acid homeostasis and drug metabolism. Arch Biochem Biophys 433, 397-412

Date of publication: Spring 2010; Nuclear Receptor Resource Newsletter

Author information: Jack Vanden Heuvel, PhD

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