Selective glucocorticoid receptor nonsteroidal ligands completely antagonize the dexamethasone mediated induction of enzymes involved in gluconeogenesis and glutamine metabolism

Einstein, Monica; Greenlee, Mark L.; Rouen, Greg; Sitlani, Ayesha; Santoro, Joe; Wang, Chuanlin; Pandit, Shilpa; Mazur, Paul; Smalera, Isabella; Weaver, Alehna P. M.; Zeng, Ying Ying; Ge, Lan; Kelly, Theresa M.; Paiva, Tony; Geissler, Wayne M.; Mosley, Ralph T.; Williamson, Joanne M.; Ali, Amjad; Balkovec, Jim; Harris, G.

doi:10.1016/j.jsbmb.2004.10.009

Cited by 20 publications

(13 citation statements)

References 26 publications

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“…on bone metabolism and/or glucose control) are reduced relative to their antiinflammatory activities (Schacke et al 2004;Einstein et al 2004). They have been variously described as selective glucocorticoid receptor agonists (SEGRAs), ''dissociated steroids'' or ''selective modulators'' (Miner 2002;Coghlan et al 2003a, b;Schacke et al 2007;Spies et al 2010).…”

Section: Commentsmentioning

confidence: 99%

Anti-inflammatory glucocorticoid drugs: reflections after 60 years

Whitehouse

2010

Inflammopharmacol

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This review considers the problem of the serious concomitant side effects of powerful anti-inflammatory drugs modelled upon the principal human glucocorticoid hormone, cortisol. The very nature of the original bio-assays to validate their cortisol-like hormonal and anti-inflammatory activities ensured that pleiotropic toxins were selected for clinical studies. Other complicating factors have been (1) considerable reliance on bio-assays conducted in laboratory animals that primarily secrete corticosterone, not cortisol, as their principal anti-inflammatory adrenal hormone; (2) some differences in the binding of xenobiotic cortisol analogues (vis á vis cortisol) to transport proteins, detoxifying enzymes and even some intra-cellular receptors; (3) the "rogue" properties of these hormonal xenobiotics, acting independently of--but still able to suppress--hormonal mechanisms regulating endogenous cortisol; and (4) problems of intrinsic/acquired "steroid resistance", diminishing their clinical efficacy, but not necessarily all their toxicities. The rather gloomy conclusion is that devising new drugs to reproduce the effect of multi-potent hormones may be a recipe for disaster, in contexts other than simply remedying an endocrine deficiency. Promising new developments include "designed" combination therapies that allow some reduction in total steroid doses (and hopefully their side effects); sharpening strategies to limit the actual duration of steroid administration; and resurgent interest in searching for more selective analogues (both steroidal and non-steroid) with less harmful side effects. Some oversights and neglected areas of research are also considered. Overall, it now seems timely to engage in some drastic rethinking about (retaining?) these "licensed toxins" as fundamental therapies for chronic inflammation.

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Section: Commentsmentioning

confidence: 99%

Anti-inflammatory glucocorticoid drugs: reflections after 60 years

Whitehouse

2010

Inflammopharmacol

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“…For example the realization that GR induce gluconeogenetic enzymes like tyrosine aminotransferase, phosphoenolpyruvate carboxykinase, and glucose-6-phosphatase, or the glucose transporter 2 lead to the assumption that deactivators antagonizing GR activity should lower plasma glucose concentrations and therefore result in antidiabetic actions. This concept could be verified for the antagonist RU486 [123,124]. Literature sources give evidence for the intensive research going on to identify novel antagonists e.g.…”

Section: Physiological and Pathophysiological Functions Of The Grmentioning

confidence: 85%

Predicting Drug Metabolism Induction In Silico

Schuster¹,

Steindl²,

Langer³

2006

CTMC

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The inducibility of drug-metabolizing enzymes and transporters by numerous xenobiotics has become a vital issue to be considered in the drug development process. Activation of so-called orphan nuclear receptors has been identified to result in increased expression of these detoxifying systems and consequently altered drug levels in the human body. In order to anticipate such mechanisms already in early stages of drug design and to avoid dangerous drug-drug interactions, reliable in silico simulation tools are highly desirable. This review aims to give an introduction into induction of drug metabolism and transport and focuses on computer-assisted molecular modeling prediction techniques, on their applicability and limitations, on recent case studies, and on success stories.

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“…Jacobson et al [103] showed that suppression of GR activity in liver is sufficient to have a strong impact on glucose levels in OB/OB mice (a model of mouse diabetes). This implies that a similar effect might be detectable in patients with diabetes that is dependent on the relative importance of hepatic glucose production versus insulin insensitivity, dietary glucose and pancreatic function [104].…”

Section: Antagonistsmentioning

confidence: 95%

New and improved glucocorticoid receptor ligands

Miner

Hong

Negro‐Vilar

2005

Expert Opinion on Investigational Drugs

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The therapeutic and prophylactic use of glucocorticoids is widespread due to their powerful anti-inflammatory, antiproliferative and immunomodulatory activity. However, long-term use of these drugs can result in severe dose-limiting side effects. One of the most critical and debilitating side effects is osteoporosis, which leads to increased risk of fractures. Glucocorticoids damage bone through several different mechanisms. The search for novel glucocorticoids that have reduced side effects in bone and other tissues is being driven by the identification of new mechanisms of action of the glucocorticoid receptor. This may facilitate the detection of new, safer therapies with efficacies equivalent to currently prescribed steroids.

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Selective glucocorticoid receptor nonsteroidal ligands completely antagonize the dexamethasone mediated induction of enzymes involved in gluconeogenesis and glutamine metabolism

Cited by 20 publications

References 26 publications

Anti-inflammatory glucocorticoid drugs: reflections after 60 years

Anti-inflammatory glucocorticoid drugs: reflections after 60 years

Predicting Drug Metabolism Induction In Silico

New and improved glucocorticoid receptor ligands

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