Biochemical and computational insights into the anti-aromatase activity of natural catechol estrogens

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. (c) 2008 Elsevier Ltd. All rights reserved.