Antiepileptic Drugs Affect Neuronal Androgen Signaling via a Cytochrome P450-Dependent Pathway

Gehlhaus, Marcel; Schmitt, Nina; Volk, Benedikt; Meyer, Ralf Peter

doi:10.1124/jpet.107.120303

Cited by 20 publications

(15 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Though previous efforts have failed to detect the AR receptor in PC12 cells by RT-PCR (Nguyen et al, 2005), we did in fact demonstrate AR receptor expression in both rat brain (as a control) and in neuron-like PC12 cells growing in culture, supporting the findings of other investigators (Gehlhaus et al, 2007; Meyer et al, 2009) and in a distribution pattern similar to that identified through confocal microscopy in prior publications (Caraci et al, 2011). While androgens can exert rapid non-genomic effects involving induction of second messenger signal transduction cascades, these lipophilic hormones also induce AR dimerization and translocation into the nucleus where the complex engages in direct protein-protein interaction with transcriptional co-regulators at cognate palindromic response elements to promote the expression of target genes.…”

Section: Discussionsupporting

confidence: 91%

“…To determine if PC12 cells also express this receptor after differentiation and induction of a neuron-like phenotype, we performed immunocytochemistry for AR on NGF treated PC12 in culture. We observed AR expression in the cytoplasm (Figure 1C), which under higher magnification exhibited a peri-nuclear pattern of expression (Figures 1C, inset , and 1D), contrary to a prior report (Nguyen et al, 2005) but in accordance with others (Gehlhaus et al, 2007; Meyer et al, 2009). These results indicate that PC12 express the receptor for androgens that could be mediating the pathway for AAS to affect cell physiology.…”

Section: Resultssupporting

confidence: 58%

See 1 more Smart Citation

Supraphysiological doses of performance enhancing anabolic-androgenic steroids exert direct toxic effects on neuron-like cells

Basile¹,

Binmadi²,

Zhou³

et al. 2013

Front. Cell. Neurosci.

View full text Add to dashboard Cite

Anabolic-androgenic steroids (AAS) are lipophilic hormones often taken in excessive quantities by athletes and bodybuilders to enhance performance and increase muscle mass. AAS exert well known toxic effects on specific cell and tissue types and organ systems. The attention that androgen abuse has received lately should be used as an opportunity to educate both athletes and the general population regarding their adverse effects. Among numerous commercially available steroid hormones, very few have been specifically tested for direct neurotoxicity. We evaluated the effects of supraphysiological doses of methandienone and 17-α-methyltestosterone on sympathetic-like neuron cells. Vitality and apoptotic effects were analyzed, and immunofluorescence staining and western blot performed. In this study, we demonstrate that exposure of supraphysiological doses of methandienone and 17-α-methyltestosterone are toxic to the neuron-like differentiated pheochromocytoma cell line PC12, as confirmed by toxicity on neurite networks responding to nerve growth factor and the modulation of the survival and apoptosis-related proteins ERK, caspase-3, poly (ADP-ribose) polymerase and heat-shock protein 90. We observe, in contrast to some previous reports but in accordance with others, expression of the androgen receptor (AR) in neuron-like cells, which when inhibited mitigated the toxic effects of AAS tested, suggesting that the AR could be binding these steroid hormones to induce genomic effects. We also note elevated transcription of neuritin in treated cells, a neurotropic factor likely expressed in an attempt to resist neurotoxicity. Taken together, these results demonstrate that supraphysiological exposure to the AAS methandienone and 17-α-methyltestosterone exert neurotoxic effects by an increase in the activity of the intrinsic apoptotic pathway and alterations in neurite networks.

show abstract

Section: Discussionsupporting

confidence: 91%

Section: Resultssupporting

confidence: 58%

Supraphysiological doses of performance enhancing anabolic-androgenic steroids exert direct toxic effects on neuron-like cells

Basile¹,

Binmadi²,

Zhou³

et al. 2013

Front. Cell. Neurosci.

View full text Add to dashboard Cite

show abstract

“…However, mRNA and protein expression for AR have been reported [138,139]. This difference in AR expression could be due to Glutamax supplementation, since the media and serum used are similar to what is used in our laboratory [138,139] (Table 2). …”

Section: Introductionmentioning

confidence: 96%

Cell Models for the Study of Sex Steroid Hormone Neurobiology

Rybalchenko²,

Schreihofer³

et al. 2012

J Steroids Hormon Sci

View full text Add to dashboard Cite

To date many aspects of neurons and glia biology remain elusive, due in part to the cellular and molecular complexity of the brain. In recent decades, cell models from different brain areas have been established and proven invaluable toward understanding this complexity. In the field of steroid hormone neurobiology, an important question is: what is the profile of steroid hormone receptor expression in these specific cell lines? Currently, a clear summary of such receptor profiling is lacking. For this reason, we summarized in this review the expression of estrogen, progesterone, and androgen receptors in several widely used cell lines (glial and neuronal) derived from the forebrain and midbrain, based on our own data and that from the literature. Such information will aid in the selection of specific cell lines used to test hypotheses related to the biology of estrogens, progestins, and/or androgens.

show abstract

“…In patients with HCC, the alterations in lipid and lipoprotein metabolism can be clearly observed (30). AR has been demonstrated to be associated with hepatocarcinogenesis and HCC development (1,3,(5)(6)(7)9,10). The present study revealed that AR could serve a role in hepatocarcinogenesis via the regulation of hepatocellular fatty acid metabolism.…”

Section: Discussionmentioning

confidence: 61%

“…AR is a transcription factor activated via ligand-dependent and ligand-independent mechanisms (8). Cytochrome P450, transforming growth factor β1, vascular endothelial growth factor A and heat shock protein family A member 5 are target genes of ARs in the liver (3,7,9,10). Crosstalk between ARs and liver X receptor (nuclear receptor subfamily 1 group H member 2) has also been implicated in maintaining cholesterol homeostasis (11).…”

Section: Introductionmentioning

confidence: 99%

Overexpression of the androgen receptor in human hepatoma cells and its effect on fatty acid metabolism

et al. 2017

View full text Add to dashboard Cite

Abstract. Hepatocellular carcinoma (HCC) is a predominantly male disease in which the androgen receptor (AR) serves an important pathogenic role in hepatocarcinogenesis. Fatty acid metabolism also contributes to hepatocarcinogenesis and is associated with the prognosis of cancer. The present study aimed to investigate the effects of the AR on fatty acid metabolism-associated gene expression in human hepatoma cell lines. AR-expression plasmids or control plasmids were transiently transfected into the human HCC cell lines Huh7 and HepG2. After 48 h, cellular protein and RNA were extracted and the expression of AR was confirmed by western blotting. Complementary DNA was synthesized and subjected to a quantitative polymerase chain reaction-based array to examine the expression of 84 fatty acid metabolism-associated genes. Overexpression of AR significantly downregulated the expression of 11 fatty acid metabolism-associated genes in Huh7 cells and 35 in HepG2 cells. The overexpression of AR also resulted in the upregulation of 6 fatty acid metabolism genes in HepG2 cells; however, it had no effect in Huh7 cells. Acyl-coenzyme A (CoA) thioesterase 7 and acyl-CoA oxidase 3 were downregulated in both cell lines. In conclusion, upregulation of AR via overexpression led to the disturbance of fatty acid metabolism-associated gene expression in human HCC cells. Therefore, the AR may serve a role in hepatocarcinogenesis via the regulation of hepatocellular fatty acid metabolism.

show abstract

Antiepileptic Drugs Affect Neuronal Androgen Signaling via a Cytochrome P450-Dependent Pathway

Cited by 20 publications

References 38 publications

Supraphysiological doses of performance enhancing anabolic-androgenic steroids exert direct toxic effects on neuron-like cells

Supraphysiological doses of performance enhancing anabolic-androgenic steroids exert direct toxic effects on neuron-like cells

Cell Models for the Study of Sex Steroid Hormone Neurobiology

Overexpression of the androgen receptor in human hepatoma cells and its effect on fatty acid metabolism

Contact Info

Product

Resources

About