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https://hdl.handle.net/10316/5837
Title: | Biochemical and computational insights into the anti-aromatase activity of natural catechol estrogens | Authors: | Neves, Marco A. C. Dinis, Teresa C. P. Colombo, Giorgio Melo, M. Luísa Sá e |
Keywords: | Breast cancer; Aromatase inhibition; Estradiol metabolites; Catechol estrogens; Structure-activity relationships; Electrostatic surface potential | Issue Date: | 2008 | Citation: | The Journal of Steroid Biochemistry and Molecular Biology. 110:1-2 (2008) 10-17 | Abstract: | High levels of endogenous estrogens are associated with increased risks of breast cancer. Estrogen levels are mainly increased by the activity of the aromatase enzyme and reduced by oxidative/conjugative metabolic pathways. In this paper, we demonstrate for the first time that catechol estrogen metabolites are potent aromatase inhibitors, thus establishing a link between aromatase activity and the processes involved in estrogen metabolism. In particular, the anti-aromatase activity of a set of natural hydroxyl and methoxyl estrogen metabolites was investigated using biochemical methods and subsequently compared with the anti-aromatase potency of estradiol and two reference aromatase inhibitors. Catechol estrogens proved to be strong inhibitors with an anti-aromatase potency two orders of magnitude higher than estradiol. A competitive inhibition mechanism was found for the most potent molecule, 2-hydroxyestradiol (2-OHE2) and a rational model identifying the interaction determinants of the metabolites with the enzyme is proposed based on ab initio quantum-mechanical calculations. A strong relationship between activity and electrostatic properties was found for catechol estrogens. Moreover, our results suggest that natural catechol estrogens may be involved in the control mechanisms of estrogen production. | URI: | https://hdl.handle.net/10316/5837 | DOI: | 10.1016/j.jsbmb.2007.10.011 | Rights: | openAccess |
Appears in Collections: | FFUC- Artigos em Revistas Internacionais |
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