Torcetrapib induces aldosterone and cortisol production by an intracellular calcium-mediated mechanism independently of cholesteryl ester transfer protein inhibition.
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Hu X, Dietz JD, Xia C, Knight DR, Loging WT, Smith AH, Yuan H, Perry DA, Keiser J
Torcetrapib induces aldosterone and cortisol production by an intracellular calcium-mediated mechanism independently of cholesteryl ester transfer protein inhibition.
Endocrinology. 2009 May;150(5):2211-9. doi: 10.1210/en.2008-1512. Epub 2009 Jan 22.
- PubMed ID
- 19164467 [ View in PubMed]
- Abstract
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.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Torcetrapib Cytochrome P450 11B2, mitochondrial Protein Humans UnknownInducerDetails - Pharmaco-transcriptomics
Drug Drug Groups Gene Gene ID Change Interaction Chromosome Colforsin Experimental Investigational CYP11B1 1584 upregulated Colforsin results in increased expression of CYP11B1 mRNA 8q24.3 Colforsin Experimental Investigational CYP11B2 1585 upregulated Colforsin results in increased expression of CYP11B2 mRNA 8q24.3 Torcetrapib Investigational CREM 1390 upregulated torcetrapib results in increased expression of CREM mRNA 10p11.21 Torcetrapib Investigational CYP11B1 1584 upregulated torcetrapib results in increased expression of CYP11B1 mRNA 8q24.3 Torcetrapib Investigational CYP11B2 1585 upregulated torcetrapib results in increased expression of CYP11B2 mRNA 8q24.3 Torcetrapib Investigational CYR61 3491 upregulated torcetrapib results in increased expression of CYR61 mRNA 1p22.3 Torcetrapib Investigational GEM 2669 upregulated torcetrapib results in increased expression of GEM mRNA 8q22.1 Torcetrapib Investigational NR4A1 3164 upregulated torcetrapib results in increased expression of NR4A1 mRNA 12q13.13 Torcetrapib Investigational NR4A2 4929 upregulated torcetrapib results in increased expression of NR4A2 mRNA 2q22-q23 Torcetrapib Investigational NR4A3 8013 upregulated torcetrapib results in increased expression of NR4A3 mRNA 9q22 Torcetrapib Investigational PPIA 5478 upregulated torcetrapib results in increased expression of PPIA mRNA 7p13 Torcetrapib Investigational RHOB 388 upregulated torcetrapib results in increased expression of RHOB mRNA 2p24.1 Torcetrapib Investigational USP4 7375 upregulated torcetrapib results in increased expression of USP4 mRNA 3p21.31 Torcetrapib Investigational ZNF331 55422 upregulated torcetrapib results in increased expression of ZNF331 mRNA 19q13