Methylation of 2-hydroxyestradiol in isolated organs

Lefteris C. Zacharia, Raghvendra K. Dubey, Zaichuai Mi, Edwin K. Jackson

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Vascular smooth muscle and glomerular mesangial cells in culture express a biochemical pathway that methylates 2-hydroxyestradiol (17β-estradiol metabolite) to produce 2-methoxyestradiol, a cell growth inhibitor that may mediate the cardiorenal protective effects of 17β-estradiol. Whether this pathway exists in intact organ systems is currently unclear. Accordingly, the purpose of the present investigation was to characterize the methylation of 2-hydroxestradiol in intact organs from both male and female rats. No significant differences were detected in the ability of male and female tissues to methylate 2-hydroxyestradiol. In isolated hearts, kidneys, and mesenteries perfused with Tyrode's solution, Km values for 2-hydroxyestradiol methylation were 0.175±0.021, 0.387±0.054, and 0.495±0.089 μmol/L, respectively, and Vmax values were 21.0±1.58, 24.9±1.49, and 1.01±0.148 pmol 2-methoxyestradiol · min-1 · ml-1 per gram, respectively. The catalytic efficiency (Vmax/Km) was greatest in the heart compared with the kidney and mesentery (132±14.3, 78.4±15.1, and 2.30±0.263 pmol 2-methoxyestradiol · min-1 · mL-1 · μmol/L-1 per gram, respectively). In the kidney, the catechol-O-methyltransferase inhibitor quercetin and norepinephrine (10 μmol/L) reduced methylation of 2-hydroxyestradiol by approximately 90% and 41%, respectively. Importantly, methylation in the kidney was inhibited by an average of 16.6±1.80% by endogenous norepinephrine released by renal artery nerve stimulation. Our results indicate that a robust 2-hydroxyestradiol methylation pathway exists in the kidney and heart, but not in the mesentery, and that this pathway is mediated by catechol-O-methyltransferase. Our findings also suggest that catecholamines may interfere with 2-hydroxyestradiol methylation and thereby attenuate the cardiorenal protective effects of 17β-estradiol.

Original languageEnglish
Pages (from-to)82-87
Number of pages6
JournalHypertension
Volume42
Issue number1
DOIs
Publication statusPublished - 1 Jul 2003

Keywords

  • Catecholamines
  • Coronary artery disease
  • Renal disease
  • Sympathetic nervous system
  • Vascular diseases

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