Xenobiotics and the Glucocorticoid Receptor

Journal Article · Wed Mar 15 00:00:00 EDT 2017 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/J.TAAP.2017.02.003· OSTI ID:22690943

Gulliver, Linda S M, E-mail: [e-mail]

Glucocorticoid Receptor (GR) is present in virtually every human cell type. Representing a nuclear receptor superfamily, GR has several different isoforms essentially acting as ligand-dependent transcription factors, regulating glucocorticoid-responsive gene expression in both a positive and a negative manner. Although the natural ligand of the Glucocorticoid Receptor, glucocorticoids (GC) represent only some of the multiple ligands for GR. Xenobiotics, ubiquitous in the environment, bind to GR and are also capable of activating or repressing GR gene expression, thereby modulating GR cell and tissue-specific downstream effects in a multitude of ways that include responses to inflammatory, allergic, metabolic, neoplastic and autoimmune processes. Many xenobiotics, if inadequately metabolized by xenobiotic metabolizing enzymes and not wholly eliminated, could have deleterious toxic effects with potentially lethal consequences. This review examines GR, the genomic and non-genomic actions of natural and synthetic GC and the body's handling of xenobiotic compounds, before reviewing what is presently known about GR's interactions with many of the more commonly encountered and some of the less well known GR-associated xenobiotics. GR promiscuity and crosstalk with other signaling pathways is discussed, alongside novel roles for GR that include mood disorder and addiction. A knowledge of GR interactions with xenobiotics is increasingly relevant when considering aging populations and the related prevalence of neoplastic disease, together with growing concerns around human exposure to mixtures of chemicals in the environment. Furthermore, escalating rates of obesity, Type 2 diabetes; autoimmune, allergy, addiction and mood disorder-related pathologies, require novel targeted interventions and GR appears a promising pharmacological candidate. - Highlights: • Biological impact of xenobiotics acting through Glucocorticoid Receptor. • Promiscuity of Glucocorticoid Receptor. • Involvement of Glucocorticoid Receptor in multiple pathologies. • Novel xenobiotic ligands for Glucocorticoid Receptor. • Potential for multifaceted Glucocorticoid Receptor-targeted pharmacological interventions.

• OSTI ID: 22690943
• Journal Information: Toxicology and Applied Pharmacology, Vol. 319; Other Information: Copyright (c) 2017 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ACTH
ANDROGENS
AROMATICS
CESIUM FLUORIDES
DIOXIN
ENVIRONMENTAL PROTECTION
ESTROGENS
ETHERS
GLOBULINS
GLUCOCORTICOIDS
GLYCEROL
GLYCOGEN
GLYCOLS
HISTONES
HYDROXYLASES
LEUKOCYTES
LIBERINS
LIGANDS
MACROPHAGES
METABOLIC DISEASES
NEOPLASMS
NITRIC OXIDE
PHOSPHATES
PHOSPHOTRANSFERASES
PROGESTERONE
RECEPTORS
REVIEWS
SKELETON
TRANSCRIPTION FACTORS
TYROSINE
XENOBIOTICS