Genomic Profiling in Nuclear Receptor-Mediated Toxicity

Abstract

Nuclear receptors (NRs) are attractive drug targets due to their role in regulation of a wide range of physiologic responses. In addition to providing therapeutic value, many pharmaceutical agents along with environmental chemicals are ligands for NRs and can cause adverse health effects that are directly related to activation of NRs. Identifying the molecular events that produce a toxic response may be confounded by the fact that there is a significant overlap in the biological processes that NRs regulate. Microarrays and other methods for gene expression profiling have served as useful, sensitive tools for discerning the mechanisms by which therapeutics and environmental chemicals invoke toxic effects. The capability to probe thousands of genes simultaneously has made genomics a prime technology for identifying drug targets, biomarkers of exposure/toxicity and key players in the mechanisms of disease. The complex intertwining networks regulated by NRs are hard to probe comprehensively without global approaches and genomics has become a key technology that facilitates our understanding of NR-dependent and -independent events. The future of drug discovery, design and optimization, and risk assessment of chemical toxicants that activate NRs will inevitably involve genomic profiling. This review will focus on genomics studies related to PPAR, CAR, PXR, RXR, LXR, FXR, and AHR.

DEHP: Genotoxicity and potential carcinogenic mechanisms—A review

“…However, the field of cancer research has been transformed by discoveries of epigenetic changes and their role in cancer and chronic disease states [195]. Pathways rather than individual genes appear to govern the course of tumorigenesis with the same phenotype arising from alterations in any of several genes [205]. Pathway alterations can occur by epigenomic mechanisms rather than mutation, as cell phenotype is not only dependent on genotype but also on its unique epigenotype.…”

Apoptotic and neurotoxic actions of 4-para-nonylphenol are accompanied by activation of retinoid X receptor and impairment of classical estrogen receptor signaling

“…It may also exert its actions via binding to the xenobiotic receptors: constitutive androstane receptor (CAR) and pregnane X receptor (PXR) that are known to mediate the actions of various xenobiotics [30,31]. ERs and xenobiotic receptors are involved in regulating development, morphogenesis, organogenesis, reproduction, metabolism and homeostasis [32][33][34][35]. These nuclear receptors are able to directly bind to DNA response elements: EREs (estrogen response elements) and XREs (xenobiotic response elements), leading to the transcriptional activation of target genes [36].…”

Endothelial cellular senescence is inhibited by liver X receptor activation with an additional mechanism for its atheroprotection in diabetes

“…In humans, 48 different types of nuclear receptors have been identified. These include the receptor for a metabolite of vitamin A, retinoic acid, retinoic acid receptor (RAR); the vitamin D receptor (VDR); the fatty acid receptor, peroxisome proliferator-activated receptor γ (PPARγ); the oxysterol receptor, liver X receptor (LXR); and their obligate heterodimeric partner, the retinoid X receptor (RXR) (2,3). LXRs act as potent transcriptional switches for the coordinated regulation of genes involved in the control of hepatic lipid and cholesterol metabolism, and have a crucial role in reverse cholesterol transport, thereby stimulating of cholesterol efflux from the peripheral tissue to the liver (4).…”