QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.103.060426v1 308/3/1165    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by de Medina, P. Articles by Poirot, M. Search for Related Content PubMed PubMed Citation Articles by de Medina, P. Articles by Poirot, M.

CARDIOVASCULAR

Tamoxifen Is a Potent Inhibitor of Cholesterol Esterification and Prevents the Formation of Foam Cells

Département Innovation Thérapeutique et Oncologie Moléculaire, Centre de Physiopathologie de Toulouse Purpan, Institut National de la Santé et de la Recherche Médicale Unité 563, Institut Claudius Regaud, Toulouse Cedex, France (P.D.M., B.L.P., S.S.P., G.F., J.C.F., M.P.); Laboratoire de la Signalisation et de la Différenciation des Macrophages, Institut Louis Bugnard, CHU Rangueil, Toulouse Cedex, France (J.B., B.P.); Centre de Microscopie Électronique Appliquée à la Biologie, Faculté de Médecine de Rangueil, Toulouse Cedex, France (B.L.P.); and Affichem, Ramonville-Saint-Agne, France (I.B.).

Tamoxifen is a selective estrogen receptor modulator (SERM) used for the treatment and prevention of breast cancer. Tamoxifen has been reported to protect against the progression of coronary artery diseases in human and different atherosclerosis animal models by blocking the appearance of the atheromatous plaque. However, the molecular mechanism of this effect remains unknown. Acyl-CoA:cholesterol acyl transferase (ACAT) catalyzes the biosynthesis of cholesteryl esters, which are the major lipids found in the atheromatous plaque. In this paper we have tested whether ACAT might be inhibited by tamoxifen. We show, using molecular modeling, that tamoxifen displays three-dimensional structural homology with Sah 58-035 (3-[decyldimethylsilyl]-N-[2-(4-methylphenyl)-1-phenylethyl]-propanamide), a prototypical inhibitor of ACAT. We report that tamoxifen inhibits ACAT in a concentration-dependent manner on rat liver microsomal extract. We show that the presence on estrogen receptor ligands of a backbone isosteric to the diphenyl ethane backbone of Sah 58-035 constitutes a pharmacophore for ACAT inhibition. More importantly, tamoxifen was able to inhibit ACAT on intact macrophages stimulated with acetylated low-density lipoproteins and blocked the formation of foam cells, a step that precedes the formation of the atheromatous plaque. This work constitutes the first evidence that tamoxifen is an inhibitor of ACAT and foam cell formation at therapeutic doses and that this may account for its atheroprotective action.

Address correspondence to: Marc Poirot, Département Innovation Thérapeutique et Oncologie Moléculaire, Institut Claudius Regaud, INSERM U 563, CPTP, 20-24 rue du Pont Saint Pierre, 31052 Toulouse Cedex, France. E-mail: poirot{at}icr.fnclcc.fr

This article has been cited by other articles:

				B. Payre, P. de Medina, N. Boubekeur, L. Mhamdi, J. Bertrand-Michel, F. Terce, I. Fourquaux, D. Goudouneche, M. Record, M. Poirot, et al. Microsomal antiestrogen-binding site ligands induce growth control and differentiation of human breast cancer cells through the modulation of cholesterol metabolism Mol. Cancer Ther., December 1, 2008; 7(12): 3707 - 3718. [Abstract] [Full Text] [PDF]

				T. C. Rideout, Z. Yuan, M. Bakovic, Q. Liu, R.-K. Li, Y. Mine, and M. Z. Fan Guar Gum Consumption Increases Hepatic Nuclear SREBP2 and LDL Receptor Expression in Pigs Fed an Atherogenic Diet J. Nutr., March 1, 2007; 137(3): 568 - 572. [Abstract] [Full Text] [PDF]

				P. de Medina, N. Boubekeur, P. Balaguer, G. Favre, S. Silvente-Poirot, and M. Poirot The Prototypical Inhibitor of Cholesterol Esterification, Sah 58-035 [3-[Decyldimethylsilyl]-N-[2-(4-methylphenyl)-1-phenylethyl]propanamide], Is an Agonist of Estrogen Receptors J. Pharmacol. Exp. Ther., October 1, 2006; 319(1): 139 - 149. [Abstract] [Full Text] [PDF]

				O. A. Gudbrandsen, T. H. Rost, and R. K. Berge Causes and prevention of tamoxifen-induced accumulation of triacylglycerol in rat liver J. Lipid Res., October 1, 2006; 47(10): 2223 - 2232. [Abstract] [Full Text] [PDF]

				D. J. Grainger and P. M. Schofield Tamoxifen for the Prevention of Myocardial Infarction in Humans: Preclinical and Early Clinical Evidence Circulation, November 8, 2005; 112(19): 3018 - 3024. [Full Text] [PDF]

				J. P. Conway and M. Kinter Proteomic and Transcriptomic Analyses of Macrophages with an Increased Resistance to Oxidized Low Density Lipoprotein (oxLDL)-induced Cytotoxicity Generated by Chronic Exposure to oxLDL Mol. Cell. Proteomics, October 1, 2005; 4(10): 1522 - 1540. [Abstract] [Full Text] [PDF]

				B. Kedjouar, P. de Medina, M. Oulad-Abdelghani, B. Payre, S. Silvente-Poirot, G. Favre, J.-C. Faye, and M. Poirot Molecular Characterization of the Microsomal Tamoxifen Binding Site J. Biol. Chem., August 6, 2004; 279(32): 34048 - 34061. [Abstract] [Full Text] [PDF]