Figure 1

Estrogen metabolism by cytochrome P450 1A2 (CYP1A2) and its postulated effects on catecholestrogen levels and mammographic density. ^aCYP1A2 is principally responsible for metabolizing 17β-estradiol after an initial conversion to estrone. The enzyme is primarily involved in 2- and 4-hydroxylations. ^bIn humans, between 40% and 50% of estrogens undergo 2-hydroxylation whereas 5–8% undergo 4-hydroxylation. ^cCatecholestrogens are deactivated by catechol-O-methyltransferase (COMT). ^dCatecholestrogens can potentially affect breast density levels through estrogen-receptor mediated mechanisms and/or oxidative mechanisms. 2-Hydroxyestrogens are nonestrogenic and nontumorigenic, but can be oxidized to form predominantly stable DNA adducts. 4-Hydroxyestrogens are estrogenic and carcinogenic. They form potentially genotoxic and cytotoxic reactive oxygen species (ROS) that can bind to DNA to create depurinating adducts. ROS can also participate in lipid peroxidation to create the mutagen malondialdehyde (MDA), which is a risk factor for mammographic density. These mechanisms are postulated to be inhibitory (-) or stimulatory (+) for development of mammographic density.