Cytochrome P450 1A2 (CYP1A2) Activity and Risk Factors for Breast Cancer: A Cross-Sectional Study

Chi-Chen Hong; Bing-Kou Tang; Geoffrey L Hammond; David Tritchler; Martin Yaffe; Norman F Boyd


Breast Cancer Res. 2004;6(4) 

In This Article

Abstract and Introduction

Introduction: Breast cancer risk may be determined by various genetic, metabolic, and lifestyle factors that alter sex hormone metabolism. Cytochrome P450 1A2 (CYP1A2) is responsible for the metabolism of estrogens and many exogenous compounds, including caffeine.
Methods: In a cross-sectional study of 146 premenopausal and 149 postmenopausal women, we examined the relationships between CYP1A2 activity and known or suspected risk factors for breast cancer. Blood levels of sex hormones, lipids, and growth factors were measured. In vivo CYP1A2 activity was assessed by measuring caffeine metabolites in urine. Stepwise and maximum R regression analyses were used to identify covariates related to CYP1A2 activity after adjustment for ethnicity.
Results: In both menopausal groups CYP1A2 activity was positively related to smoking and levels of sex hormone binding globulin. In premenopausal women, CYP1A2 activity was also positively related to insulin levels, caffeine intake, age, and plasma triglyceride levels, and negatively related with total cholesterol levels and body mass index. In postmenopausal women CYP1A2 activity was positively associated with insulin-like growth factor-1, and negatively associated with plasma triglyceride, high-density lipoprotein cholesterol, and age at menarche.
Conclusion: These results suggest that CYP1A2 activity is correlated with hormones, blood lipids, and lifestyle factors associated with breast cancer risk, although some of the observed associations were contrary to hypothesized directions and suggest that increased CYP1A2 function may be associated with increased risk for breast cancer.

Epidemiologic evidence suggests that endocrine factors alter breast cancer risk. In both premenopausal and postmenopausal women cancer risk is associated with events that alter hormonal balance, such as age at menarche, parity, body weight, body fat distribution, and use of exogenous hormones. Prospective data from postmenopausal women have also shown that modest increases (+15%) in circulating sex hormone levels are associated with increased future risk for developing breast cancer.[1]

Exposure to sex hormones may be affected by various genetic, metabolic, and lifestyle factors that can alter the biosynthesis and metabolism of sex hormones. Function of the cytochrome P450 1A2 (CYP1A2) enzyme might play a role in determining estrogen exposure because it is principally responsible for the metabolism of 17β-estradiol after initial conversion to estrone. CYP1A2 is a major phase I enzyme, and accounts for about 15% of total liver P450 content.[2] The enzyme is most active in catalyzing 2-hydroxylations,[3] and in humans between 40% and 50% of estrogens are hydroxylated at the C-2 position.[4] Increased formation of 2-hydroxylated estrogens would be consistent with a reduced risk for breast cancer under a 'receptor-mediated' hypothesis because 2-hydroxyestrogens can bind only weakly to the estrogen receptor.[5] Higher CYP1A2 activity is therefore postulated to be associated with reduced risk for breast cancer.

Previous research has shown that CYP1A2 activity can be influenced by a number of factors including use of exogenous hormones, body size, tobacco smoke., and intake of coffee and cruciferous vegetables.[6,7,8] The rate of estrogen 2-hydroxylation can also be influenced by dietary factors.[9] The goal of the present study, conducted in a cross-sectional sample of 295 women, was to identify the determinants and covariates of CYP1A2 activity, particularly those related to breast cancer risk. These include potential associations with reproductive events, sex hormone levels, the growth hormone (GH)/insulin-like growth factor (IGF)-1 axis, body size, plasma lipids, smoking status, and diet.

In vivo CYP1A2 function was examined by assessing caffeine clearance. Caffeine is a good probe for CYP1A2 function because 90% of caffeine clearance is mediated by CYP1A2.[10] Urinary caffeine metabolites have been used to calculate a number of ratios that indicate CYP1A2 function. We chose to use the caffeine metabolic ratio (CMR), which is calculated as follows: CMR = (5-acetylamino-6-formylamino-3-methyluracil [AFMU] + 1-methylurate [1U] + 1 methylxanthine [1X])/1, 7-dimethylurate (1,7U). This is because this parameter is not dependent on renal flow[11] and is based only on metabolic end products of caffeine metabolism, thus making the amount and timing of urine collection relatively unimportant.[10] Measurement of the CMR in 24-hour urine samples has been shown to be a viable method of assessing CYP1A2 intake in populations with widespread caffeine use.[12] In the present study 93% of women consumed sufficient levels of caffeine to estimate CMR. Because daily caffeine intake is relatively constant, urinary recovery of caffeine metabolites over a 24-hour period reflects CMRs observed with standardized dosing.[12]


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