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

Disclosures

Breast Cancer Res. 2004;6(4) 

In This Article

Results

Of 357 (182 premenopausal and 175 postmenopausal) women who consented to participate in the study, 40 (11.2%; 29 premenopausal and 11 postmenopausal) did not have urine samples and 22 (6.2%; seven premenopausal and 15 postmenopausal) had insufficient excretion of caffeine metabolites for estimating CYP1A2 activity. This left 146 postmenopausal women and 149 postmenopausal women in whom CYP1A2 activity was measurable, representing 93% of those with urine samples and 83% of eligible women. The overall participation rate for this portion of the study was 77% (295/382).

Selected characteristics of the 146 premenopausal and 149 postmenopausal study participants with CYP1A2 phenotype data are shown according to ethnicity in Table 1 and Table 2 , respectively. Of the women studied, 85% were Caucasian, 3.4% were East Asian, 5.1% were Jewish, and 6.4% were from other ethnic groups. The mean age was 45 years in premenopausal and 56 years in postmenopausal women. The two groups were similar in age at menarche, age at first birth, total number of live births, insulin levels, and daily caffeine and total energy intake. Postmenopausal women had higher average BMI and WHR, and lower circulating levels of estradiol, SHBG and IGF-1, lower levels of percentage mammographic density, and higher levels of free estradiol, IGFBP-3, and total plasma cholesterol and triglycerides.

Compared with Caucasians, premenopausal and postmenopausal East Asian women and premenopausal Jewish women had lower mean BMIs, lower levels of total and free estradiol, higher levels of SHBG, and greater percentage breast density. Among premenopausal women, both East Asians and Jewish women had lower levels of circulating insulin than did Caucasians, and Jewish women also had lower IGF-1 levels. In postmenopausal women, compared with Caucasians, East Asians were older at age of first birth and had higher levels of CYP1A2 activity, and Jewish women had lower CYP1A2 activity, higher levels of SHBG, IGF-1, and insulin, and lower levels of daily energy intake.

In premenopausal women, those without CYP1A2 data had slightly lower SHBG and IGF-1 levels. In postmenopausal women, those without CYP1A2 results weighed less, and had lower BMIs and WHRs, and lower levels of total blood cholesterol and triglycerides. Mammographic density, estradiol, SHBG, and IGF-1 levels were also higher in postmenopausal women without CYP1A2 results.

In premenopausal women the CMR ranged from 0.77 to 23.5, with a mean ± standard deviation of 6.21 ± 2.86 and a median of 5.84. In postmenopausal women the ratio ranged from 1.84 to 17.06 with a mean ± standard deviation of 5.85 ± 2.32, and median of 5.40. This magnitude of interindividual variation is similar to that in previous reports showing up to a 30-fold variation in enzyme activity.[25,26] The population distribution of CMR in the present study was log-normal, and similar to that in other studies using the same urinary ratio.[7,12,26]

When CYP1A2 activity was compared between different ethnic groups ( Table 1 and Table 2 ), there was some indication, based on small numbers, that Jewish women may have lower CMRs than Caucasians (premenopausal 5.0 ± 1.0, postmenopausal 3.5 ± 1.7). Postmenopausal East Asian women (n = 6) were observed to have a higher mean CMR than Caucasian women (8.9 ± 1.8). This, however, was likely to have occurred by chance due to low numbers because previous studies generally showed CYP1A2 function to be lower[27] or not different[7] between Orientals and Caucasians.

Table 3 and Table 4 show relationships between CYP1A2 activity and known or suspected risk factors for breast cancer. Ethnicity, age, body size (BMI and WHR), and smoking status as determinants of CYP1A2 activity[7] were included in all models as potential confounders. For variables associated with CYP1A2 activity at P ≤ 0.20, quartile least square means were determined for descriptive purposes.

CYP1A2 activity was not related to menopausal status (P = 0.51; data not shown) or to age at menopause in postmenopausal women (P = 0.57). CYP1A2 activity was not related to parity (P > 0.61; data not shown) or age at first full-term pregnancy (P > 0.46) in either menopausal groups, but in postmenopausal women was negatively associated with age (P = 0.04) and age at menarche (P = 0.05). Adjusted mean CYP1A2 activities were 17.3% and 14.8% lower for postmenopausal women in the fourth quartile of age (P for trend = 0.02) and age at menarche (P for trend = 0.04), respectively, compared with those in the first quartile.

BMI was inversely associated with CYP1A2 activity in premenopausal (P = 0.03) but not in postmenopausal women (P = 0.75). In premenopausal women, despite a significant P value for trend (P for trend 0.04), mean CMR was higher only for women in the lowest quartile of BMI (7.76) as compared with the other quartiles (6.11–6.17). There was some evidence that WHR was positively associated with CYP1A2 activity in premenopausal women (P = 0.07), and inversely related to CYP1A2 activity in postmenopausal women (P = 0.02). Mean CMRs were respectively 22.2% higher and 9.7% lower in premenopausal and postmenopuasal women for those in the highest quartile of WHR as compared with those in the lowest quartile.

Lifestyle factors examined were smoking and diet. Smoking is known to induce CYP1A2 activity,[7] and as expected smokers had higher CYP1A2 activity than did nonsmokers. Compared with nonsmokers, mean CMR was 55.6% higher in premenopausal smokers and 54.3% higher in postmenopausal smokers (data not shown).

Of the nutritional variables examined, caffeine (P = 0.01), total energy intake (P = 0.02), fat intake (P = 0.04), and protein intake (P = 0.006) were positively associated with CYP1A2 activity in premenopausal women. Of these, only caffeine (P for trend = 0.02) and total energy intake (P for trend 0.06) exhibited significant or borderline significant associations based on tests for trend across quartiles of intake. Compared with women in the lowest quartiles, mean CMRs were 21.2% and 18.8% higher, respectively, for women in the highest quartile of caffeine and total energy intake. In postmenopausal women, CYP1A2 activity did not vary with caffeine intake or any of the other dietary components tested.

CYP1A2 activity was not associated with total estradiol (P > 0.53), progesterone (P > 0.53), or follicle-stimulating hormone (P > 0.44) levels in either menopausal group. CYP1A2 activity was, however, negatively associated with percentage free estradiol in both premenopausal (P = 0.001) and postmenopausal (P = 0.03) women. Mean CMRs were respectively 22% and 15% lower for premenopausal (P for trend = 0.007) and postmenopausal (P for trend = 0.01) women in the highest quartile of circulating estradiol levels compared with women in the lowest quartile. A positive association with SHBG was observed for premenopausal women (P = 0.001), in which women in the highest quartile of SHBG levels had a 31.2% higher mean CMR than did women in the lowest quartile (P for trend 0.004).

GH levels were not associated with CYP1A2 activity in either menopausal groups (P = 0.45). For premenopausal women, a positive relationship was observed between endogenous insulin levels and CYP1A2 activity (P = 0.01). Those in the highest quartile had a 39.9% higher mean CMR than did those in the lowest quartile. The test for trend was also significant (P = 0.0009). No other associations were observed. In postmenopausal women, CYP1A2 activity was positively related to IGF-1 levels (P = 0.01), negatively associated with its main binding protein IGFBP-3 (P = 0.005), and not associated with endogenous insulin levels (P = 0.92). Mean CMRs were only raised for women in the highest quartile of IGF-1, at 7.5 (+15 to 19%), as compared with mean CMRs of 6.3–6.5 in the first three quartiles; the test for trend was not statistically significant (P = 0.13). Women in the highest quartile for IGFBP-3 had a 25.2% lower mean CMR than did those in the lowest quartile.

In premenopausal women, CYP1A2 activity was inversely associated with total plasma cholesterol (P = 0.0003), LDL-cholesterol (P = 0.004) and HDL-cholesterol (P = 0.07) levels, but not with triglyceride levels (P = 0.83). Tests for trends, however, were only significant for total (P = 0.006) and LDL (P = 0.004) cholesterol. Mean CMRs were 23.5% and 28.0% lower for women in the highest quartile of total cholesterol and LDL-cholesterol, respectively, as compared with those in the lowest quartile. In contrast, no statistically significant relationships were detected between CYP1A2 activity in postmenopausal women and plasma LDL-cholesterol, although borderline negative relationships were observed for total cholesterol (P = 0.06) and triglyceride levels (P = 0.07). Mean CMRs for women in the highest quartile of total cholesterol (P for trend = 0.05) and blood triglyceride levels (P for trend = 0.15) were 12.2% and 11.4% lower, respectively, than for women in the lowest quartile.

Family history of breast cancer was not significantly related to CYP1A2 activity in either premenopausal or postmenopausal women (data not shown; P > 0.10).

Stepwise and maximum R regression analyses were used to identify covariates related to CYP1A2 activity after controlling for any mutual confounding. All variables shown in Table 3 and Table 4 , as well as smoking status, were included in the models except those that were highly correlated (see Statistical methods section, above, for details). Findings are shown in Table 5 and Table 6 .

In both menopausal groups CYP1A2 activity was positively related to smoking (P < 0.0001) and SHBG (P ≤ 0.004). In premenopausal women CYP1A2 activity was also positively related to endogenous insulin levels (P = 0.008), caffeine intake (P = 0.007), age (P = 0.03) and plasma triglyceride levels (P = 0.04), and negatively related to total cholesterol levels (P = 0.0003) and BMI (P = 0.04). All tests for trend across quartiles for each variable were significant except for blood triglycerides (P for trend = 0.24). In postmenopausal women, CYP1A2 activity was positively associated with IGF-1 levels (P = 0.03), and negatively associated with plasma triglyceride (P = 0.0001) and HDL-cholesterol levels (P = 0.002), and age at menarche (P = 0.02). All tests for trend across quartiles of each variable were significant except for IGF-1 (P for trend = 0.22). Of the variance in CYP1A2 activity, 42% and 41% was explained in premenopausal and postmenopausal women, respectively.

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