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(Circulation. 2003;108:2974.)
© 2003 American Heart Association, Inc.

Brief Rapid Communications

Methoxyestradiols Mediate the Antimitogenic Effects of 17ß-Estradiol

Direct Evidence From Catechol-O-Methyltransferase–Knockout Mice

Lefteris C. Zacharia, PhD; Joseph A. Gogos, MD, PhD; Maria Karayiorgou, MD; Edwin K. Jackson, PhD; Delbert G. Gillespie, BS; Federica Barchiesi, PhD; Raghvendra K. Dubey, PhD

From the Center for Clinical Pharmacology, Departments of Medicine (L.C.Z., E.K.J., D.G.G., R.K.D.) and Pharmacology (E.K.J.), University of Pittsburgh, Pittsburgh, Pa; the Department of Obstetrics and Gynecology, University Hospital, Zurich, Switzerland (F.B., R.K.D.); and the Laboratory of Human Neurogenetics, Rockefeller University (M.K.), and Department of Physiology and Cellular Biophysics, Center for Neurobiology and Behavior, Columbia University (J.A.G.), New York, NY.

Correspondence to Dr Raghvendra K. Dubey, Clinic for Endocrinology (D217, NORD-1), University Hospital Zurich, Frauenklinikstrasse 10, 8091 Zurich, Switzerland. E-mail raghvendra.dubey{at}usz.ch

Received September 29, 2002; revision received October 27, 2003; accepted October 30, 2003.

Background— Studies using pharmacological agents suggest but do not prove that the antimitogenic effects of estradiol are caused by conversion of estradiol to hydroxyestradiols (mediated by CYP450s) followed by methylation of hydroxyestradiols to methoxyestradiols (mediated by catechol-O-methyltransferase, COMT).

Methods and Results— To test this hypothesis more rigorously, we used aortic smooth muscle cells (SMCs) from mice lacking COMT (COMT-KO). Wild-type (WT) but not COMT-KO SMCs efficiently converted 2-hydroxyestradiol to 2-methoxyestradiol. Both WT and COMT-KO SMCs expressed estrogen receptors. Estradiol and 2-hydroxyestradiol concentration-dependently inhibited serum-induced DNA synthesis, cell numbers, and collagen synthesis in WT but not COMT-KO SMCs. 2-Methoxyestradiol inhibited DNA synthesis, cell numbers, and collagen synthesis in both WT and COMT-KO SMCs.

Conclusions— These data provide strong evidence that the vascular antimitogenic effects of estradiol are estrogen receptor–independent and involve the sequential conversion of estradiol to hydroxyestradiols and then to methoxyestradiols.

Key Words: coronary disease • hormones • metabolism • muscle, smooth • receptors

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