McKay L, Renoir JM, Weigel NL, Wilson EM, McDonnell DP, Cidlowski JA (2006 Dec) International Union of Pharmacology. LXV. The pharmacology and classification of the nuclear receptor superfamily: glucocorticoid, mineralocorticoid, progesterone, and androgen receptors. Pharmacol Rev

Molecular Endocrinology Group, Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709, USA.
Pharmacological Reviews (Impact Factor: 17.1). 01/2007; 58(4):782-97. DOI: 10.1124/pr.58.4.9
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    • "These chemicals include natural and synthetic glucocorticoids (GCs). Synthetic GCs are currently used as pharmaceuticals to treat a wide variety of health conditions in humans and in veterinary medicine including inflammatory and immune diseases, such as asthma, rheumatic disease, inflammatory bowel disease, allergies, and eye and skin diseases (Barnes, 2010; Lu et al., 2006). After consumption, GCs are released into the environment, primarily via wastewater. "
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    ABSTRACT: Glucocorticoids (GCs) are widely used as anti-inflammatory drugs. Our previous study demonstrated that several GCs such as cortisol and dexamethasone (Dex) were frequently detected in effluents collected from Japanese sewage treatment plants (STPs) in 2012. In this study, we used the GC-Responsive Chemical-Activated LUciferase gene eXpression (GR-CALUX) assay to elucidate GC receptor (GR) agonistic activities of ten pure synthetic GCs and selected STP effluents in Japan for assessment of the risks associated with the presence of GR agonists. The tested GCs demonstrated dose-dependent agonistic effects in the GR-CALUX assay and their EC50 values were calculated for estimation of relative potencies (REPs) compared to Dex. The GR agonistic potency was in the rank of: clobetasol propionate>clobetasone butyrate>betamethasone 17-valerate>difluprednate>betamethasone 17,21-dipropionate>Dex>betamethasone>6α-methylprednisolone>prednisolone>cortisol. The GR agonistic activity in STP effluents as measured in Dex-equivalent (Dex-EQ) activities ranged from <3.0-78ngL(-1) (median: 29ngL(-1), n=50). To evaluate the contribution of the target GCs, theoretical Dex-EQs were calculated by multiplying the concentrations of each GC by its respective REP. Our calculation of Dex-EQ contribution for individual GR agonists indicated that the well-known GCs cortisol and Dex should not be given priority for subsequent in vivo testing, monitoring and removal experiments, but rather the highly potent synthetic GCs clobetasol propionate and betamethasone 17-valerate (REP=28 and 3.1) as well as other unidentified compounds are important GR agonists in STP effluents in Japan. Copyright © 2015 Elsevier B.V. All rights reserved.
    Science of The Total Environment 05/2015; 527-528C:328-334. DOI:10.1016/j.scitotenv.2015.05.008 · 4.10 Impact Factor
    • "There is also evidence for " fast " actions (seconds or minutes) of GR and MR due to membrane-bound versions of the receptors (Haller et al., 2008; Evanson et al., 2010; Prager et al., 2010; Hammes and Levin, 2011). In contrast to widespread GR expression, MR expression is restricted to specific brain nuclei important for both HPA and pain regulation, such as the hippocampus, PVN, and amygdala (Lu et al., 2006); studies suggest that both the cytoplasmic and membrane versions are present in those nuclei (Johnson et al., 2005; Karst et al., 2005; Evanson et al., 2010; Prager et al., 2010). Thus, the balanced activation between the " slow " transcriptional and " fast " membrane GR and MR effects produces the appropriate response to an acute stressor. "
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    ABSTRACT: While current therapeutics provide relief from acute pain, drugs used for treatments of chronic pain are typically less efficacious and limited by adverse side effects including tolerance, addiction and gastrointestinal upset. Thus, there is a significant need for novel therapies for the treatment of chronic pain. In concert with chronic pain, persistent stress facilitates pain perception and sensitizes pain pathways, leading to a feed-forward cycle promoting chronic pain disorders. Stress-exacerbation of chronic pain suggests that centrally acting drugs targeting the pain and stress responsive brain regions represent a valid target for the development of novel therapeutics. This review will provide an overview of how stress modulates spinal and central pain pathways, identify key neurotransmitters and receptors within these pathways, and highlight their potential as novel therapeutics to treat chronic pain.
    Journal of Pharmacology and Experimental Therapeutics 09/2014; 351(2). DOI:10.1124/jpet.114.218065 · 3.97 Impact Factor
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    • "Moreover, the 21-hydroxylase protein was observed in all the analyzed samples from GD 15.5 to PN 16. This is important because the substrate of this enzyme, progesterone, is present during gestation while the product of this enzyme, DOC, has the ability to bind the glucocorticoid receptor [12-15] with an IC50 value of 70 nM compared to 60 nM for corticosterone [15]. Therefore, the developing lung possesses the machinery to produce active glucocorticoids, at least during gestation, using circulating progesterone as a substrate. "
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    ABSTRACT: Glucocorticoids exert recognized positive effects on lung development. The genes involved in the classical pathway of glucocorticoid synthesis normally occurring in adrenals were found to be expressed on gestation day (GD) 15.5 in the developing mouse lung. Recently, expression of two of these genes was also detected on GD 17.5 suggesting a more complex temporal regulation than previously expected. Here, we deepen the knowledge on expression of "adrenal" glucocorticoid synthesis genes in the mouse lung during the perinatal period and we also study expression of the gene encoding for the steroid inactivating enzyme 20alpha-hydroxysteroid dehydrogenase (20alpha-HSD). We performed an ontogenic study of P450scc, 3beta-hydroxysteroid dehydrogenase/Delta5-Delta4 isomerase 1 (3beta-HSD1), 21-hydroxylase, 11beta-hydroxylase, 11beta-HSD1, and 11beta-HSD2 expression up to post natal day (PN) 15. The substrate (progesterone) and the product (deoxycorticosterone) of 21-hydroxylase are substrates of 20alpha-HSD, thus 20alpha-HSD (Akr1c18) gene expression was investigated. In lung samples collected between GD 15.5 and PN 15, 11beta-hydroxylase was only detected on GD 15.5. In contrast, all the other tested genes were expressed throughout the analyzed period with different temporal expression patterns. P450scc, 21-hydroxylase, 20alpha-HSD and 11beta-HSD2 mRNA levels increased after birth with different patterns including an increase from PN 3 with a possible sex difference for 21-hydroxylase mRNA. Also, the 21-hydroxylase protein was observed by Western blot in perinatal lungs with higher levels after birth. Progesterone is present at high levels during gestation and the product of 21-hydroxylase, deoxycorticosterone, can bind the glucocorticoid receptor with an affinity close to that of corticosterone. Detection of 21-hydroxylase at the protein level during antenatal lung development is the first evidence that the adrenal-like glucocorticoid synthesis pathway detected during lung development has the machinery to produce glucocorticoids in the fetal lung. Glucocorticoids from lung 21-hydroxylase appear to modulate lung ontogenesis through paracrine/intracrine actions.
    BMC Research Notes 03/2014; 7(1):119. DOI:10.1186/1756-0500-7-119
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