Torcetrapib induces aldosterone and cortisol production by an intracellular calcium-mediated mechanism independently of cholesteryl ester transfer protein inhibition.
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.
Hu
Xiao
X
St. Louis Laboratories, Pfizer Global Research and Development, 700 Chesterfield Parkway West, Chesterfield, Missouri 63017, USA. xiao.hu@pfizer.com
Dietz
Jessica D
JD
Xia
Chunsheng
C
Knight
Delvin R
DR
Loging
William T
WT
Smith
Andrew H
AH
Yuan
Haodan
H
Perry
David A
DA
Keiser
Joan
J
D000310:Adrenal Gland Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000450:Aldosterone / Q000378:metabolism*; D000924:Anticholesteremic Agents / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors*; D019405:Cytochrome P-450 CYP11B2 / Q000235:genetics / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism*; D007424:Intracellular Fluid / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D011804:Quinolines / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D013252:Steroid 11-beta-Hydroxylase / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
D000924:Anticholesteremic Agents; D053480:Cholesterol Ester Transfer Proteins; D011804:Quinolines; D000450:Aldosterone; C483909:torcetrapib; D019405:Cytochrome P-450 CYP11B2; D013252:Steroid 11-beta-Hydroxylase; D006854:Hydrocortisone