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(Hypertension. 2003;41:807.)
© 2003 American Heart Association, Inc.

Scientific Contributions

CYP450- and COMT-Derived Estradiol Metabolites Inhibit Activity of Human Coronary Artery SMCs

Raghvendra K. Dubey; Delbert G. Gillespie; Lefteris C. Zacharia; Federica Barchiesi; Bruno Imthurn; Edwin K. Jackson

From the Department of Obstetrics and Gynecology, Clinic for Endocrinology, University Hospital Zurich (R.K.D., F.B., B.I.), Switzerland; Department of Medicine (R.K.D., D.G.G., L.C.Z., B.I., E.K.J.) and Department of Pharmacology (E.K.J.), Center for Clinical Pharmacology, University of Pittsburgh Medical Center, Pittsburgh, Penn.

Correspondence 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 rag{at}fhk.usz.ch

The purpose of this study is to test the hypothesis that the inhibitory effects of estradiol in human coronary vascular smooth muscle cells are mediated via local conversion to methoxyestradiols via specific cytochrome P_450s (CYP450s) and catechol-O-methyltransferase (COMT). The inhibitory effects of estradiol on serum-induced cell activity (DNA synthesis, cell number, collagen synthesis, and cell migration) were enhanced by 3-methylcholantherene, phenobarbital (broad-spectrum CYP450 inducers), and ß-naphthoflavone (CYP1A1/1A2 inducer) and were blocked by 1-aminobenzotriazole (broad-spectrum CYP450 inhibitor). Ellipticine, -naphthoflavone (selective CYP1A1 inhibitors), and pyrene (selective CYP1B1 inhibitor), but not ketoconazole (selective CYP3A4 inhibitor) or furafylline (selective CYP1A2 inhibitor), abrogated the inhibitor effects of estradiol on cell activity, a profile consistent with a CYP1A1/CYP1B1-mediated mechanism. The inhibitory effects of estradiol were blocked by the COMT inhibitors OR486 and quercetin. The estrogen receptor antagonist ICI 182,780 blocked the inhibitory effects of estradiol, but only at concentrations that also blocked the metabolism of estradiol to hydroxyestradiols (precursors of methoxyestradiols). Western blot analysis revealed that coronary smooth muscle cells expressed CYP1A1 and CYP1B1. Moreover, these cells metabolized estradiol to hydroxyestradiols and methoxyestradiols, and the conversion of 2-hydroxyestradiol to 2-methoxyestradiol was blocked by OR486 and quercetin. These findings provide evidence that the inhibitory effects of estradiol on coronary smooth muscle cells are largely mediated via CYP1A1- and CYP1B1-derived hydroxyestradiols that are converted to methoxyestradiols by COMT.

Key Words: hormones • menopause • estrogen • metabolism • coronary artery disease • remodeling • cardiovascular diseases

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