Published Online
on December 19, 2005

A more recent version of this article appeared on March 1, 2006

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Submitted on September 28, 2005
Revised on October 11, 2005

Regulation of Peroxisome Proliferator-Activated Receptor Activity by Losartan Metabolites

Michael Schupp; Lucas D. Lee; Nikolaj Frost; Sumaira Umbreen; Boris Schmidt; Thomas Unger; and Ulrich Kintscher^*

From the Center for Cardiovascular Research (M.S., L.D.L., N.F., T.U., U.K.), Institute of Pharmacology and Toxicology, Charité-Universitätsmedizin Berlin, Berlin, Germany; Division of Endocrinology, Diabetes, and Metabolism (M.S.), Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pa; and Technical University (S.U., B.S.), Institute for Organic Chemistry and Biochemistry, Darmstadt, Germany.

^* To whom correspondence should be addressed. E-mail: ulrich.kintscher{at}charite.de.

Abstract--Two active metabolites of the angiotensin type 1 (AT₁) receptor blocker losartan have been described previously, EXP3174 and EXP3179. Whereas EXP3174 is the main antihypertensive AT₁ receptor-blocking metabolite, the role of EXP3179 is widely unknown. Recently, a subgroup of AT₁ receptor blockers has been identified as ligands for the peroxisome proliferator-activated receptor (PPAR-). Here we characterize the PPAR--activating properties of the 2 active losartan metabolites. PPAR- activity was measured with a chimeric Gal4-DNA-binding domain-hPPAR-ligand-binding domain (LBD) fusion protein on a Gal4-dependent luciferase reporter system. EXP3179 prominently induced the activation of the PPAR--LBD reaching a maximum at 100 µmol/L with a 7.1±1-fold induction (P<0.05 versus vehicle-treated cells). Maximum PPAR--LBD activation by EXP3179 reached 51% of the maximum response induced by the full PPAR- agonist pioglitazone, identifying EXP3179 as a partial PPAR- agonist. EXP3174 did not induce PPAR--LBD activation. EC₅₀ values were calculated for PPAR--LBD activity (pioglitazone EC₅₀: 0.88 µmol/L; EXP3179 EC₅₀: 17.1 µmol/L; losartan EC₅₀: >50 µmol/L). Consistent with the activation of PPAR-, EXP3179 potently induced 3T3-L1 adipocyte differentiation, a typical PPAR--dependent cell function, and markedly stimulated PPAR- target gene expression. EXP3174 failed to regulate differentiation or PPAR- target gene expression. The present study characterizes the active losartan metabolite EXP3179 as a partial PPAR- agonist. PPAR- activation by EXP3179 may help us to understand the beneficial metabolic effects of losartan observed in clinical trials.

Key words: diabetes mellitus • insulin resistance • angiotensin antagonists

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