Rifampicin Is Not an Activator of Glucocorticoid Receptor

Herr, Alexandra S.; Wochnik, Gabriela M.; Rosenhagen, M.; Holsboer, Florian; Rein, T.

doi:10.1124/mol.57.4.732

Cited by 41 publications

(26 citation statements)

References 36 publications

(46 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Of course, this model implies that GR activation by antidepressants is independent from inhibition of MDR PGP, as it seems to be present in the abcb1ab (À/À) mice. It is possible that abcb1ab (À/À) mice express other transporters that regulate the access of glucocorticoids to neuronal cells and that could be inhibited by antidepressants, like the MDR-associated protein (MRP or ABCC1) (Herr et al, 2000;Hirrlinger et al, 2002;Sisodiya et al, 2002). Indeed, we have recently described that the tricyclic antidepressant, clomipramine, increases the intracellular concentration of glucocorticoids in rat cortical neurons, where MDR PGP has not been described (Pariante et al, 2003a).…”

Section: Discussionmentioning

confidence: 99%

The Antidepressant Desipramine Requires the ABCB1 (Mdr1)-Type p-Glycoprotein to Upregulate the Glucocorticoid Receptor in Mice

Yau

Noble

Thomas

et al. 2007

Neuropsychopharmacol

View full text Add to dashboard Cite

The mechanisms by which antidepressants regulate the hypothalamic-pituitary-adrenal (HPA) axis are still unknown. The ABCB1-type multiple drug resistance (MDR) p-glycoprotein (PGP) regulates the HPA axis by limiting the access of glucocorticoids to the brain in mice and humans. Previous work in cell cultures has found that antidepressants enhance glucocorticoid receptor (GR) function in vitro by inhibiting MDR PGP, and therefore by increasing the intracellular concentration of glucocorticoidsFbut this model has never been tested directly in animals. Here, the tricyclic antidepressant, desipramine (20 mg/kg/day, i.p., for seven days), was administered to abcb1ab MDR PGP knockout mice (congenic on the FVB/N background strain) and to FVB/N controls. The hippocampal mRNA expression of GR, mineralocorticoid receptor (MR), MDR (Mdr1a) PGP, and 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1) were measured, together with plasma corticosterone levels. In FVB/N controls, desipramine induced a significant upregulation of GR mRNA in the CA1 region ( + 31%; p ¼ 0.045); in contrast, in abcb1ab (À/À) mice, desipramine induced a significant downregulation of GR mRNA in the CA1 region (À45%; p ¼ 0.004). MR mRNA expression was unaltered. Desipramine decreased corticosterone levels in both FVB/N controls and in abcb1ab (À/À) mice, but in abcb1ab (À/À) mice the effects were smaller. Specifically, in FVB/N controls (but not in abcb1ab (À/À) mice), desipramine reduced corticosterone levels not only compared with saline-treated mice but also compared with the 'physiological' levels of untreated mice (À39%; p ¼ 0.05). Finally, desipramine reduced Mdr1a mRNA expression across all hippocampus areas (À9 to À23%), but had no effect on 11b-HSD1 mRNA expression. These data support the notion that the MDR PGP is one of the molecular targets through which antidepressants regulate the HPA axis.

show abstract

Section: Discussionmentioning

confidence: 99%

The Antidepressant Desipramine Requires the ABCB1 (Mdr1)-Type p-Glycoprotein to Upregulate the Glucocorticoid Receptor in Mice

Yau

Noble

Thomas

et al. 2007

Neuropsychopharmacol

View full text Add to dashboard Cite

show abstract

“…Luciferase and ␤-galactosidase assays were performed as described before (17). All experiments were carried out in duplicates.…”

Section: Methodsmentioning

confidence: 99%

Cofilin 1 Is Revealed as an Inhibitor of Glucocorticoid Receptor by Analysis of Hormone-Resistant Cells

Rüegg

Holsboer

Turck

et al. 2004

Molecular and Cellular Biology

Self Cite

View full text Add to dashboard Cite

Significant knowledge about glucocorticoid signaling has accumulated, yet many aspects remain unknown. We aimed to discover novel factors involved in glucocorticoid receptor regulation that do not necessarily require direct receptor interaction. We achieved this by using a functional genetic screen: a stable cell line which cannot survive hormone treatment was engineered, randomly mutated, and selected in the presence of glucocorticoid. A hormone-resistant clone was analyzed by two-dimensional gel electrophoresis. Differentially expressed proteins were identified and tested as candidates for regulation of the glucocorticoid receptor. An unexpected candidate, cofilin 1, inhibited receptor activity. Cofilin is known to promote actin depolymerization and filament severing. Several experiments suggest that this feature of cofilin is involved in its inhibitory action. Both its actin depolymerization activity and its inhibitory action on the receptor are dependent on its phosphorylation state. Treatment of cells with a cytoskeleton-disrupting agent decreased receptor activity, as did overexpression of actin, particularly a mutant actin that does not polymerize. In addition, overexpression of cofilin and actin as well as chemical cytoskeleton disruption changed the subcellular receptor distribution and upregulated c-Jun, which could constitute the inhibitory mechanism of cofilin. In summary, cofilin represents a novel factor that can cause glucocorticoid resistance.

show abstract

“…Rifampin has long been considered an immunosuppressive drug. However, despite the many studies describing its immunosuppressive activities (15,21,25,27,32,35), physicians have been puzzled by the lack of clinically relevant immunosuppressive adverse effects, even during prolonged treatment and in patients with AIDS (10,12). Additionally, rifampin activates the nuclear pregnane X receptor (PXR) of the cytochrome P-450 enzymes that metabolize drugs in the liver (23,30).…”

mentioning

confidence: 99%

Effect of Rifampin on Production of Inflammatory Mediators in HepG2 Liver Epithelial Cells

Yuhas

Berent

Ashkenazi

2011

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Rifampin, a potent antibacterial agent, is one of the main drugs used in the treatment of mycobacterial infections. Hepatotoxicity is a well-documented adverse event. The aim of this study was to investigate the effect of rifampin on the production of inflammatory mediators in human epithelial HepG2 liver cells in the absence or presence of proinflammatory cytokines. Incubation of HepG2 cells with a cytokine mix plus rifampin was associated with a significant dose-dependent increase in the production of nitric oxide compared to incubation with the cytokine mix alone (P < 0.05) as well as with an increase in inducible nitric oxide synthase protein and mRNA expression. Rifampin significantly increased the secretion of interleukin 8 (IL-8) in both untreated cells (P < 0.001) and cytokine-treated cells (P < 0.006). An array screening assay revealed that rifampin stimulated the production of IL-1␤ and gamma interferon-induced protein-10 (IP-10) in untreated cells and increased the secretion of RANTES in cytokine-treated cells. Together, these results indicate that rifampin may exert proinflammatory effects on liver cells.

show abstract

Rifampicin Is Not an Activator of Glucocorticoid Receptor

Cited by 41 publications

References 36 publications

The Antidepressant Desipramine Requires the ABCB1 (Mdr1)-Type p-Glycoprotein to Upregulate the Glucocorticoid Receptor in Mice

The Antidepressant Desipramine Requires the ABCB1 (Mdr1)-Type p-Glycoprotein to Upregulate the Glucocorticoid Receptor in Mice

Cofilin 1 Is Revealed as an Inhibitor of Glucocorticoid Receptor by Analysis of Hormone-Resistant Cells

Effect of Rifampin on Production of Inflammatory Mediators in HepG2 Liver Epithelial Cells

Contact Info

Product

Resources

About