New mechanisms of adrenostatic compounds in a human adrenocortical cancer cell line

Fassnacht, Martin; Hahner, Stefanie; Beuschlein, Felix; Klink, Albrecht; Reincke, Martín; Allolio, Bruno

doi:10.1046/j.1365-2362.2000.0300s3076.x

Cited by 48 publications

(26 citation statements)

References 50 publications

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“…After ACTH stimulation, H295R cells showed biphasic patterns of DHEA-S secretion. This biphasic reaction to ACTH has been reported previously (Jefcoate et al 1987;Le Roy et al 2000) and was explained by the biphasic upand downregulation of ACTH receptors in H295R cells (Fassnacht et al 1998(Fassnacht et al ,2000. This was reproduced also in a forskolin stimulation experiment (data not shown).…”

Section: Discussionsupporting

confidence: 86%

Altered Expression Patterns of Heterogeneous Nuclear Ribonucleoproteins A2 and B1 in the Adrenal Cortex

Kamma

Fujiwara

et al. 2005

J Histochem Cytochem.

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S U M M A R YSeveral proteins implicated in hormonogenesis of the adrenal cortex have alternatively spliced isoforms, which respond differently to adrenocorticotropic hormone (ACTH). Heterogeneous nuclear ribonucleoproteins A2 and B1 are among the abundant pre-mRNA-binding proteins involved in alternative splicing. We examined the expression of A2 and B1 in normal adrenal cortex and tumors. B1 was variably expressed in the zona fasciculata-reticularis, although A2 was diffusely expressed in the three zones. B1 was more abundant in compact cells than clear cells, and B1 expression was frequent in the zona reticularis, which consists mainly of compact cells. In three kinds of cortical adenomas autonomously producing hormones, B1 was generally overexpressed and there were no significant differences among them. In cortisol-producing tumors, non-tumor parts of the cortex, which were generally atrophic due to low ACTH, had less B1 protein than normal adrenals. These results suggested a correlation between B1 expression and the hormonal activity responding to ACTH. In vitro ACTH stimulation induced a biphasic expression of B1 in an H295R cortical carcinoma cell line, and it paralleled hormonogenesis. Conclusively, B1 expression varied in relation to the hormonal activity responding to the ACTH, and it may provide a key to elucidating the splicing mechanisms involved in hormonogenesis.

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Section: Discussionsupporting

confidence: 86%

Altered Expression Patterns of Heterogeneous Nuclear Ribonucleoproteins A2 and B1 in the Adrenal Cortex

Kamma

Fujiwara

et al. 2005

J Histochem Cytochem.

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“…These results are in line with the results obtained by Fassnacht et al, showing CYP11B1 inhibiting effects for ETO at low concentrations (IC 50 15 nM), while at higher concentrations ETO also inhibited CYP11A1 (IC 50 400 nM), resulting in decreased levels of all steroids as observed here for 1 μM ETO. 42 This latter study also reported CYP11A1 inhibiting effects for MET with an IC 50 of 17 μM. The observed decrease in levels of pregnenolone, 17α-OHpregnenolone, and 17β-testosterone in the present study for 10 μM MET are thus in line with these previous findings.…”

Section: Evaluating the Effects Of Model Chemicals On Steroidogenesissupporting

confidence: 92%

Screening for Modulatory Effects on Steroidogenesis Using the Human H295R Adrenocortical Cell Line: A Metabolomics Approach

Rijk¹,

Peijnenburg²,

Blokland³

et al. 2012

Chem. Res. Toxicol.

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The recently OECD validated H295R steroidogenesis assay provides an in vitro alternative to evaluate the potential interference of exogenous compounds with endogenous steroid hormone synthesis. Currently, this assay is used for a simple negative-positive screening of compounds using testosterone and estradiol levels as end points, measured with specific enzyme immunoassays (EIAs) or targeted liquid chromatography (LC) and gas chromatography (GC)-mass spectrometry (MS) methods. However, recent developments in LC-MS and bioinformatics allow for more comprehensive approaches to evaluate changes in steroid profiles. In the current work, the H295R cell model was combined with a metabolomics approach to monitor changes in metabolite profiles in both a targeted and untargeted way. H295R cells were exposed for 48 h to model compounds, i.e., forskolin, abiraterone, prochloraz, ketoconazole, trilostane, formestane, aminoglutethimide, fadrozole, etomidate, and metyrapone, known to affect steroidogenesis. After exposure, the levels of 9 natural steroids were determined by a quantitative targeted GC-MS/MS method and compared to a metabolomics method using Ultra Performance Liquid Chromatography-Time-of-Flight-Mass Spectrometry (UPLC-ToF-MS). Like the EIAs, both methods were suited for negative-positive screening, but the MS methods also generated specific fingerprints, allowing chemical class prediction of the compound under investigation. Although the targeted GC-MS/MS was more sensitive, which was an advantage regarding analysis of the estrogens 17β-estradiol and estrone, the untargeted UPLC-ToF-MS was able to evaluate effects on the synthesis of the corticosteroids. Moreover, untargeted comparison of the aligned chemical profiles allowed identification of all m/z-values that are differential between exposed and nonexposed H295R cells. In conclusion, application of a comprehensive metabolite profiling methodology not only provides a tool to screen compounds for steroidogenic modulating properties, but also allows chemical class prediction. As such, steroid profiling methodologies in conjunction with the H295R assay can contribute to the prioritization of chemicals for additional safety testing.

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“…At higher doses, etomidate blocks side chain cleavage enzyme. More recent work has not only shown etomidate to potently block 11b-hydroxylase and side chain cleavage enzyme but also aldosterone synthase and may have anti-proliferative effects on adrenal cortical cells (16,17). Therefore, etomidate also has therapeutic relevance for aldosterone blockade and anti-tumorigenesis for metastatic adrenocortical tumours.…”

Section: Etomidatementioning

confidence: 99%

THERAPY IN ENDOCRINE DISEASE: Etomidate in the management of hypercortisolaemia in Cushing's syndrome: a review

Preda

Sen

Karavitaki

et al. 2012

European Journal of Endocrinology

132

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This review addresses the practical usage of intravenous etomidate as a medical therapy in Cushing's syndrome. We reviewed the relevant literature, using search terms 'etomidate', 'Cushing's syndrome', 'adrenocortical hyperfunction', 'drug therapy' and 'hypercortisolaemia' in a series of public databases. There is a paucity of large randomised controlled trials, and data on its use rely only on small series, case study reports and international consensus guideline recommendations. Based on these, etomidate is an effective parenteral medication for the management of endogenous hypercortisolaemia, particularly in cases with significant biochemical disturbance, sepsis and other serious complications such as severe psychosis, as well as in preoperative instability. We suggest treatment protocols for the safe and effective use of etomidate in Cushing's syndrome.

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New mechanisms of adrenostatic compounds in a human adrenocortical cancer cell line

Cited by 48 publications

References 50 publications

Altered Expression Patterns of Heterogeneous Nuclear Ribonucleoproteins A2 and B1 in the Adrenal Cortex

Altered Expression Patterns of Heterogeneous Nuclear Ribonucleoproteins A2 and B1 in the Adrenal Cortex

Screening for Modulatory Effects on Steroidogenesis Using the Human H295R Adrenocortical Cell Line: A Metabolomics Approach

THERAPY IN ENDOCRINE DISEASE: Etomidate in the management of hypercortisolaemia in Cushing's syndrome: a review

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