Molecular mechanisms of glucocorticoid action and resistance

Schaaf, Marcel J. M.; Cidlowski, John A.

doi:10.1016/s0960-0760(02)00263-7

Cited by 384 publications

(315 citation statements)

References 134 publications

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“…The activated drug-receptor complex rapidly translocates into the nucleus where it binds to specific palindromic sequences in the target gene, known as glucocorticoid response elements (GRE) causing either stimulation or inhibition of transcription of various genes, such as TAT. Changes in transcription rates result in alteration in specific mRNA levels, which subsequently can result in changes in proteins leading to various physiological effects exerted by CS [3,10,29]. It had been postulated that part of these receptors may undergo degradation and the rest may recycle back to the cytosol to bind to new ligand [10,30,31].…”

Section: Pharmacodynamicsmentioning

confidence: 99%

Modeling receptor/gene-mediated effects of corticosteroids on hepatic tyrosine aminotransferase dynamics in rats: dual regulation by endogenous and exogenous corticosteroids

Hazra

Pyszczynski

DuBois

et al. 2007

J Pharmacokinet Pharmacodyn

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Receptor/gene-mediated effects of corticosteroids on hepatic tyrosine aminotransferase (TAT) were evaluated in normal rats. A group of normal male Wistar rats were injected with 50 mg/kg methylprednisolone (MPL) intramuscularly at the nadir of their plasma corticosterone (CST) rhythm (early light cycle) and sacrificed at various time points up to 96 h post-treatment. Blood and livers were collected to measure plasma MPL, CST, hepatic glucocorticoid receptor (GR) mRNA, cytosolic GR density, TAT mRNA, and TAT activity. The pharmacokinetics of MPL showed bi-exponential disposition with two first-order absorption components from the injection NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript site and bioavailability was 21%. Plasma CST was reduced after MPL dosing, but resumed its daily circadian pattern within 36 h. Cytosolic receptor density was significantly suppressed (90%) and returned to baseline by 72 h resuming its biphasic pattern. Hepatic GR mRNA follows a circadian pattern which was disrupted by MPL and did not return during the study. MPL caused significant down-regulation (50%) in GR mRNA which was followed by a delayed rebound phase (60-70 h). Hepatic TAT mRNA and activity showed up-regulation as a consequence of MPL, and returned to their circadian baseline within 72 and 24 h of treatment. A mechanistic receptor/genemediated pharmacokinetic/pharmacodynamic model was able to satisfactorily describe the complex interplay of exogenous and endogenous corticosteroid effects on hepatic GR mRNA, cytosolic free GR, TAT mRNA, and TAT activity in normal rats.

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Section: Pharmacodynamicsmentioning

confidence: 99%

Modeling receptor/gene-mediated effects of corticosteroids on hepatic tyrosine aminotransferase dynamics in rats: dual regulation by endogenous and exogenous corticosteroids

Hazra

Pyszczynski

DuBois

et al. 2007

J Pharmacokinet Pharmacodyn

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“…The well-established molecular mechanisms of action for CS include the passive diffusion of the highly lipophilic CS molecule through the cell membrane and binding to the cytosolic glucocorticoid receptor, which is held inactive through the association with heat shock proteins (Schaaf and Cidlowski, 2002). Binding of the drug to the receptor causes conformational changes, phosphorylation, and activation of receptor, resulting in the formation of a homodimer of the drug receptor complex (Oakley and Cidlowski, 2011;Schaaf and Cidlowski, 2002).…”

Section: Introductionmentioning

confidence: 99%

“…Binding of the drug to the receptor causes conformational changes, phosphorylation, and activation of receptor, resulting in the formation of a homodimer of the drug receptor complex (Oakley and Cidlowski, 2011;Schaaf and Cidlowski, 2002). This activated complex translocates into the nucleus and binds to regulator sites, glucocorticoid regulatory elements (GREs) in the DNA, resulting in the regulation of transcription rate.…”

Section: Introductionmentioning

confidence: 99%

“…This activated complex translocates into the nucleus and binds to regulator sites, glucocorticoid regulatory elements (GREs) in the DNA, resulting in the regulation of transcription rate. However, in addition to direct binding, the activated complex can regulate gene expression by other mechanisms including tethering and composite binding to other transcription factors, activators, or repressors (Barnes, 1998;Schaaf and Cidlowski, 2002). Some of the critical transcription factors that are affected by CS include NF-jB, AP-1, and STAT.…”

Section: Introductionmentioning

confidence: 99%

“…Some of the critical transcription factors that are affected by CS include NF-jB, AP-1, and STAT. In addition to these genomic mechanisms, studies have shown that CS can regulate pathways by signaling through its receptor in a transcription-independent manner, although the exact mechanisms for the non-genomic effects are still unclear (Schaaf and Cidlowski, 2002).…”

Section: Introductionmentioning

confidence: 99%

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Tandem Analysis of Transcriptome and Proteome Changes after a Single Dose of Corticosteroid: A Systems Approach to Liver Function in Pharmacogenomics

Kamisoglu

Sukumaran

Nouri-Nigjeh

et al. 2015

OMICS: A Journal of Integrative Biology

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Corticosteroids (CS) such as methylprednisolone (MPL) affect almost all liver functions through multiple mechanisms of action, and long-term use results in dysregulation causing diverse side effects. The complexity of involved molecular mechanisms necessitates a systems approach. Integration of information from the transcriptomic and proteomic responses has potential to provide deeper insights into CS actions. The present report describes the tandem analysis of rich time-series transcriptomic and proteomic data in rat liver after a single dose of MPL. Hierarchical clustering of the common genes represented in both mRNA and protein datasets displayed two dominant patterns. One of these patterns exhibited complementary mRNA and protein expression profiles indicating that MPL affected the regulation of these genes at the transcriptional level. Some of the classic pharmacodynamic markers for CS actions, including tyrosine aminotransferase (TAT), were among this group, together with genes encoding urea cycle enzymes and ribosomal proteins. The other pattern was rather unexpected. For this group of genes, MPL had distinctly observable effects at the protein expression level, although a change in the reverse direction occurred at the transcriptional level. These genes were functionally associated with metabolic processes that might be essential to elucidate side effects of MPL on liver, most importantly including modulation of oxidative stress, fatty acid oxidation, and bile acid biosynthesis. Furthermore, profiling of gene and protein expression data was also done independently of one another by a two-way sequential approach. Prominent temporal shifts in expression and relevant cellular functions were described together with the assessment of changes in the complementary side.

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