Cytochrome P450 1A2 (CYP1A2) activity, mammographic density, and oxidative stress: a cross-sectional study

Abstract

Introduction: Mammographically dense breast tissue is a strong predictor of breast cancer risk, and is influenced by both mitogens and mutagens. One enzyme that is able to affect both the mitogenic and mutagenic characteristics of estrogens is cytochrome P450 1A2 (CYP1A2), which is principally responsible for the metabolism of 17beta-estradiol.

Methods: In a cross-sectional study of 146 premenopausal and 149 postmenopausal women, we examined the relationships between CYP1A2 activity, malondialdehyde (MDA) levels, and mammographic density. In vivo CYP1A2 activity was assessed by measuring caffeine metabolites in urine. Levels of serum and urinary MDA, and MDA-deoxyguanosine adducts in DNA were measured. Mammograms were digitized and measured using a computer-assisted method.

Results: CYP1A2 activity in postmenopausal women, but not in premenopausal women, was positively associated with mammographic density, suggesting that increased CYP1A2 activity after the menopause is a risk factor for breast cancer. In premenopausal women, but not in postmenopausal women, CYP1A2 activity was positively associated with serum and urinary MDA levels; there was also some evidence that CYP1A2 activity was more positively associated with percentage breast density when MDA levels were high, and more negatively associated with percentage breast density when MDA levels were low.

Conclusion: These findings provide further evidence that variation in the activity level of enzymes involved in estrogen metabolism is related to levels of mammographic density and potentially to breast cancer risk.

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.

Figure 2

Relationships between cytochrome P450 1A2 (CYP1A2) activity and percentage breast density according to (a) serum and (b) urinary malondialdehyde (MDA) levels, and (c) malondialdehyde–deoxyguanosine (dG-MDA) levels. All analyses are adjusted for age, ethnicity, body mass index (BMI), waist–hip ratio (WHR), and smoking status. Confounders were set at mean values and determined for Caucasian nonsmokers to illustrate relationships between CYP1A2 activity and percentage density according to MDA levels. Number of women in each group: premenopausal, n = 146 for serum MDA and n = 141 for urinary MDA and dG-MDA; and postmenopausal, n = 149 for serum and urinary MDA and n = 145 for dG-MDA. CMR, caffeine metabolic ratio.