Torcetrapib induces aldosterone and cortisol production by an intracellular calcium-mediated mechanism independently of cholesteryl ester transfer protein inhibition
| Autor: | Andrew H. Smith, Jessica D. Dietz, Chunsheng Xia, Haodan Yuan, Delvin R. Knight, David Austen Perry, Joan A. Keiser, Xiao Hu, William T. Loging |
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| Rok vydání: | 2009 |
| Předmět: |
Intracellular Fluid
medicine.medical_specialty Hydrocortisone medicine.drug_class Dalcetrapib Adrenal Gland Neoplasms Drug Evaluation Preclinical Blood Pressure Models Biological chemistry.chemical_compound Structure-Activity Relationship Endocrinology Internal medicine Cell Line Tumor Cholesterylester transfer protein medicine Cytochrome P-450 CYP11B2 Humans Calcium Signaling Aldosterone biology Calcium channel Anticholesteremic Agents Carcinoma Torcetrapib Angiotensin II Cholesterol Ester Transfer Proteins Gene Expression Regulation Neoplastic chemistry Mineralocorticoid biology.protein Quinolines Steroid 11-beta-Hydroxylase Evacetrapib |
| Zdroj: | Endocrinology. 150(5) |
| ISSN: | 1945-7170 |
| Popis: | ILLUMINATE (Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events), the phase 3 morbidity and mortality trial of torcetrapib, a cholesteryl ester transfer protein (CETP) inhibitor, identified previously undescribed changes in plasma levels of potassium, sodium, bicarbonate, and aldosterone. A key question after this trial is whether the failure of torcetrapib was a result of CETP inhibition or of some other pharmacology of the molecule. The direct effects of torcetrapib and related molecules on adrenal steroid production were assessed in cell culture using the H295R as well as the newly developed HAC15 human adrenal carcinoma cell lines. Torcetrapib induced the synthesis of both aldosterone and cortisol in these two in vitro cell systems. Analysis of steroidogenic gene expression indicated that torcetrapib significantly induced the expression of CYP11B2 and CYP11B1, two enzymes in the last step of aldosterone and cortisol biosynthesis pathway, respectively. Transcription profiling indicated that torcetrapib and angiotensin II share overlapping pathways in regulating adrenal steroid biosynthesis. Hormone-induced steroid production is mainly mediated by two messengers, calcium and cAMP. An increase of intracellular calcium was observed after torcetrapib treatment, whereas cAMP was unchanged. Consistent with intracellular calcium being the key mediator of torcetrapib’s effect in adrenal cells, calcium channel blockers completely blocked torcetrapib-induced corticoid release and calcium increase. A series of compounds structurally related to torcetrapib as well as structurally distinct compounds were profiled. The results indicate that the pressor and adrenal effects observed with torcetrapib and related molecules are independent of CETP inhibition. |
| Databáze: | OpenAIRE |
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