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Cytochromes 1A1/1B1- and Catechol-O-Methyltransferase-Derived Metabolites Mediate Estradiol-Induced Antimitogenesis in Human Cardiac Fibroblast

Department of Obstetrics and Gynecology, Clinic for Endocrinology, University Hospital Zurich (R.K.D., M.R., F.B., B.I.), 8091 Zurich, Switzerland; Center for Clinical Pharmacology, Departments of Medicine (R.K.D., E.K.J., D.G.G., L.C.Z., B.I.) and Pharmacology (E.K.J.), University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213-2582; Arthritis and Bone Metabolism Therapeutic Division, Novartis Pharma Research (H.K.), Basel CH-40002, Switzerland; and Institut de Gènètique et de Biologie Molèculaire et Cellulaire (A.K.), 67404 Illkirch, France

Address all correspondence and requests for reprints to: Dr. Raghvendra K. Dubey, Department of Obstetrics and Gynecology, Clinic for Endocrinology, D217, NORD-1, Frauenklinik, University Hospital Zurich, CH-8091 Zurich, Switzerland. E-mail: raghvendra.dubey{at}usz.ch.

We investigated the role of specific cytochrome P450s (CYP450s) and catechol-O-methyltransferase (COMT) in the growth inhibitory effects of estradiol in cardiac fibroblasts (CFs) expressing functional estrogen receptors. 3-Methylcholantherene, phenobarbital (broad-spectrum CYP450 inducers), and ß-naphthoflavone (CYP1A1/1A2 inducer) augmented, and 1-aminobenzotriazole (broad-spectrum CYP450 inhibitor) blocked, the inhibitory effects of estradiol on serum-induced CF growth (DNA synthesis, cell number, and collagen synthesis). Neither ketoconazole (3A4 inhibitor) nor furafylline (selective 1A2 inhibitor) altered the antimitogenic effects of estradiol on CF growth. In contrast, ellipticine (selective 1A1 inhibitor), pyrene (selective 1B1 inhibitor), and -naphthoflavone (1A1>1A2 inhibitor) abrogated the antimitogenic effects of estradiol on CF growth. OR486 (COMT inhibitor) also blocked the antimitogenic effects of estradiol in both the presence and absence of the CYP450 inducers. ICI182780 (estrogen receptor antagonist) attenuated the growth inhibitory effects of estradiol, but only at concentrations that inhibit the metabolism of estradiol to hydroxyestradiols (precursors of methoxyestradiols). CFs expressed CYP1A1 and CYP1B1, isozymes that convert estradiol to hydroxyestradiols. Moreover, CFs metabolized estradiol to hydroxyestradiol, and 2-hydroxyestradiol to 2-methoxyestradiol. OR486 and quercetin (COMT inhibitor) blocked the conversion of 2-hydroxyestradiol to 2-methoxyestradiol in CFs. We conclude that the antimitogenic effects of estradiol on CF growth are mediated in part by conversion to hydroxyestradiols via CYP1A1 and CYP1B1, followed by metabolism of hydroxyestradiols to methoxyestradiols by COMT.

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