Estrogen metabolism and breast cancer: a risk model.

摘要: Oxidative metabolites of estrogens have been implicated in the development breast cancer, yet relatively little is known about metabolism normal breast. We developed an experimental vitro model mammary estrogen which we combined purified, recombinant phase I enzymes CYP1A1 and CYP1B1 with II COMT GSTP1 to determine how 17beta-estradiol (E(2)) metabolized. employed both gas liquid chromatography mass spectrometry measure parent hormone E(2) as well eight metabolites, that is, catechol estrogens, methoxyestrogens, estrogen-GSH conjugates. used these data develop silico model, allowed kinetic simulation converting into metabolites. The simulations showed excellent agreement results provided a quantitative assessment metabolic interactions. Using rate constants genetic variants CYP1A1, CYP1B1, COMT, further examination impact enzyme polymorphisms on entire pathway, including identification those haplotypes producing largest amounts catechols quinones. Application cancer case-control population defined quinone E(2)-3,4-Q potential risk factor identified subset women increased based their consequent production. Our integrates diverse types offers exciting opportunity for researchers combine assessing estrogenic exposure relation risk.