Long-term exposure
to estrogens seriously increases the incidence
of various diseases including breast cancer. Experimental studies
indicate that cytochrome P450 (CYP) enzymes catalyze the bioactivation
of estrogens to catechols, which can exert their harmful effects via
various routes. It has been shown that the 4-hydroxylation pathway
of estrogens is the most malign, while 2-hydroxylation is considered
a benign pathway. It is also known experimentally that with increasing
unsaturation of ring B of estrogens the prevalence of the 4-hydroxylation
pathway significantly increases. In this study, we used a combination
of structural analysis, docking, and quantum chemical calculations
at the B3LYP/6-311+G* level to investigate the factors that influence
the regioselectivity of estrogen metabolism in man. We studied the
structure of human estrogen metabolizing enzymes (CYP1A1, CYP1A2,
CYP1B1, and CYP3A4) in complex with estrone using docking and investigated
the susceptibility of estrone, equilin, and equilenin (which only
differ in the unsaturation of ring B) to undergo 2- and 4-hydroxylation
using several models of CYP enzymes (Compound I, methoxy, and phenoxy
radical). We found that even the simplest models could account for
the experimental difference between the 2- and 4- hydroxylation pathways
and thus might be used for fast screening purposes. We also show that
reactivity indices, specifically in this case the radical and nucleophilic
condensed Fukui functions, also correctly predict the likeliness of
estrogen derivatives to undergo 2- or 4-hydroxylation
