Mechanisms underlying off-target effects of the cholesteryl ester transfer protein inhibitor torcetrapib involve L-type calcium channels.
OBJECTIVE
The increased mortality observed with the cholesteryl ester transfer protein inhibitor torcetrapib is partly due to increased aldosterone production and blood pressure. The mechanisms underlying these effects were investigated.


METHODS
Cytochrome P450 subunit 11B2 (aldosterone synthase), extracellular signal-regulated kinase (p44/42) and voltage-gated Cachannel alpha subunit mRNA profiling, aldosterone production, cytosolic calcium and RNA interference were assessed in adrenocarcinoma human cells (H295R). Telemetry was conducted in spontaneously hypertensive rats.


RESULTS
Torcetrapib and angiotensin II (Ang II) but not dalcetrapib (a structurally different cholesteryl ester transfer protein inhibitor) elevated both cytochrome P450 subunit 11B2 mRNA and aldosterone production in H295R cells at 6 h. At days 1-5, torcetrapib produced a sustained increase of cytochrome P450 subunit 11B2 mRNA, unlike Ang II. Although torcetrapib and Ang II potentiated the effect of 25-OH cholesterol and raised pregnenolone levels, torcetrapib increased neither cytosolic Ca at 5 min nor extracellular signal-regulated kinase1/2 phosphorylation, suggesting initially divergent pathways. Unlike Ang II, torcetrapib steroidogenesis was not affected by Ang II type 1 receptor antagonism or voltage-gated T-type Ca channel antagonism, but was blocked by several L-type Cachannel antagonists. In unbiased genome-wide screening, Ang II and torcetrapib modulated an overlapping but distinct set of genes in H295R cells. Torcetrapib, but not Ang II, upregulated mRNA levels of the L-type Ca channel alpha 1C subunit. In spontaneously hypertensive rat, torcetrapib had a potent hypertensive effect mediated by the L-type Ca channel.


CONCLUSIONS
The unique steroidogenic and hypertensive side effects of torcetrapib may be linked and involve voltage-gated L-type Ca channels. Structurally unrelated cholesteryl ester transfer protein inhibitors such as dalcetrapib do not share this effect.
Clerc
Roger G
RG
F Hoffmann-La Roche Ltd, Basel, Switzerland.
Stauffer
Andrea
A
Weibel
Franziska
F
Hainaut
Emmanuelle
E
Perez
Anne
A
Hoflack
Jean-Christophe
JC
Bénardeau
Agnès
A
Pflieger
Philippe
P
Garriz
Jose Mr
JM
Funder
John W
JW
Capponi
Alessandro M
AM
Niesor
Eric J
EJ
D000302:Adrenal Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000310:Adrenal Gland Neoplasms; D000450:Aldosterone / Q000378:metabolism; D000577:Amides; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000187:drug effects* / Q000378:metabolism; D045744:Cell Line, Tumor; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors*; D019405:Cytochrome P-450 CYP11B2 / Q000096:biosynthesis / Q000235:genetics; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D004952:Esters; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D006801:Humans; D006973:Hypertension / Q000188:drug therapy*; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D015222:Sodium Channels / Q000378:metabolism; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000494:pharmacology
D000577:Amides; D000924:Anticholesteremic Agents; D020746:Calcium Channels, L-Type; D053480:Cholesterol Ester Transfer Proteins; D004952:Esters; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D011804:Quinolines; D034741:RNA, Small Interfering; C568242:SCN1A protein, human; C568250:Scn1a protein, rat; D015222:Sodium Channels; D013438:Sulfhydryl Compounds; D000804:Angiotensin II; C411602:dalcetrapib; D000450:Aldosterone; C483909:torcetrapib; D019405:Cytochrome P-450 CYP11B2; D048049:Extracellular Signal-Regulated MAP Kinases; D002118:Calcium