help button home button Endocrine Society JCEM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2003-032154
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Reprints, Permissions and Rights
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Dubey, R. K.
Right arrow Articles by Imthurn, B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Dubey, R. K.
Right arrow Articles by Imthurn, B.
Related Collections
Right arrow Cardiovascular Endocrinology
The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 1 247-255
Copyright © 2005 by The Endocrine Society

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

Raghvendra K. Dubey, Edwin K. Jackson, Delbert G. Gillespie, Marinella Rosselli, Federica Barchiesi, Andree Krust, Hansjoerg Keller, Lefteris C. Zacharia and Bruno Imthurn

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 {alpha}-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.




This article has been cited by other articles:


Home page
 Toxicol SciHome page
S. M. Billiard, J. N. Meyer, D. M. Wassenberg, P. V. Hodson, and R. T. Di Giulio
Nonadditive effects of PAHs on Early Vertebrate Development: mechanisms and implications for risk assessment
Toxicol. Sci., September 1, 2008; 105(1): 5 - 23.
[Abstract] [Full Text] [PDF]

Home page
 Biol. Reprod.Home page
A. Parada-Bustamante, P. A Orihuela, M. Rios, P. A Navarrete-Gomez, C. A Cuevas, L. A Velasquez, M. J Villalon, and H. B Croxatto
Catechol-O-Methyltransferase and Methoxyestradiols Participate in the Intraoviductal Nongenomic Pathway Through Which Estradiol Accelerates Egg Transport in Cycling Rats
Biol Reprod, December 1, 2007; 77(6): 934 - 941.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
M. Chang, K.-w. Peng, I. Kastrati, C. R. Overk, Z.-H. Qin, P. Yao, J. L. Bolton, and G. R. J. Thatcher
Activation of Estrogen Receptor-Mediated Gene Transcription by the Equine Estrogen Metabolite, 4-Methoxyequilenin, in Human Breast Cancer Cells
Endocrinology, October 1, 2007; 148(10): 4793 - 4802.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals
Copyright © 2005 by The Endocrine Society