Etomidate unmasks intraadrenal regulation of steroidogenesis and proliferation in adrenal cortical cell lines.

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Hahner S, Sturmer A, Fassnacht M, Hartmann RW, Schewe K, Cochran S, Zink M, Schirbel A, Allolio B

Etomidate unmasks intraadrenal regulation of steroidogenesis and proliferation in adrenal cortical cell lines.

Horm Metab Res. 2010 Jun;42(7):528-34. doi: 10.1055/s-0030-1249629. Epub 2010 Mar 29.

PubMed ID

20352599 [ View in PubMed

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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 11beta-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 17alpha-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.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Etomidate	Cytochrome P450 11B1, mitochondrial	Protein	Humans	Unknown	Inhibitor	Details
Etomidate	Cytochrome P450 11B2, mitochondrial	Protein	Humans	Unknown	Inhibitor	Details