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Horm Metab Res 2010; 42(7): 528-534
DOI: 10.1055/s-0030-1249629
Original Basic

© Georg Thieme Verlag KG Stuttgart · New York

Etomidate Unmasks Intraadrenal Regulation of Steroidogenesis and Proliferation in Adrenal Cortical Cell Lines

S. Hahner1 , [*] , A. Stürmer1 , [*] , M. Fassnacht1 , R. W. Hartmann2 , K. Schewe2 , S. Cochran1 , M. Zink1 , A. Schirbel3 , B. Allolio1
  • 1Endocrinology & Diabetes Unit, Department of Medicine I, University of Würzburg, Würzburg, Germany
  • 2Pharmaceutical and Medicinal Chemistry, University of Saarland, Saarbrücken, Germany
  • 3Department of Nuclear Medicine, University of Würzburg, Würzburg, Germany
Further Information

Publication History

received 20.07.2009

accepted 22.02.2010

Publication Date:
29 March 2010 (online)

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Abstract

To characterize intraadrenal adaptations for inhibition of cortisol synthesis, we analyzed the effects of etomidate (ETO) on steroid hormone secretion and expression of key regulators of steroidogenesis and proliferation in human NCI-h295 adrenocortical cancer cells. Etomidate potently blocked 11β-hydroxylase (CYP11B1), aldosterone synthase (CYP11B2), and side chain cleavage enzyme (CYP11A1). This inhibition of steroidogenesis was associated with increased expression of steroidogenic acute regulatory protein (StAR), and CYP11A1 and 17α-hydroxylase/17, 20-lyase (CYP17A1) protein levels, but not of the respective mRNA levels. Promoter activity of CYP11A1 and melanocortin 2 receptor (MC2R) was not increased by etomidate in treated cells compared to controls. The increase in protein levels was partially reversed by cycloheximide suggesting post-transcriptional mechanisms but also protein stabilization as underlying cause. Furthermore, ETO exhibited antiproliferative activity paralleled by a decrease in phosphorylation of MEK and ERK1, 2. In summary, ETO exhibits pleiotropic effects on adrenal function in vitro. Inhibition of steroidogenesis is followed by increased levels of steroidogenic key proteins and reduced proliferation. These changes reflect adaptations to maintain steroidogenesis at the cost of adrenal proliferation.

Key words

etomidate - steroidogenic enzymes - StAR - CYP11A1 - adrenostatic compounds - proliferation

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1 Both authors contributed equally to this work.

Correspondence

B. AllolioMD 

Endocrinology & Diabetes Unit

Department of Medicine

University of Würzburg

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Email: allolio_b@medizin.uni-wuerzburg.de

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