Estrogen Metabolism and Exposure in a Genotypic–Phenotypic Model for Breast Cancer Risk Prediction

Abstract Background: Current models of breast cancer risk prediction do not directly reflect mammary estrogen metabolism or genetic variability in exposure to carcinogenic estrogen metabolites. Methods: We developed a model that simulates the kinetic effect of genetic variants of the enzymes CYP1A1, CYP1B1, and COMT on the production of the main carcinogenic estrogen metabolite, 4-hydroxyestradiol (4-OHE2), expressed as area under the curve metric (4-OHE2-AUC). The model also incorporates phenotypic factors (age, body mass index, hormone replacement therapy, oral contraceptives, and family history), which plausibly influence estrogen metabolism and the production of 4-OHE2. We applied the model to two independent, population-based breast cancer case–control groups, the German GENICA study (967 cases, 971 controls) and the Nashville Breast Cohort (NBC; 465 cases, 885 controls). Results: In the GENICA study, premenopausal women at the 90th percentile of 4-OHE2-AUC among control subjects had a risk of breast cancer that was 2.30 times that of women at the 10th control 4-OHE2-AUC percentile (95% CI: 1.7–3.2, P = 2.9 × 10−7). This relative risk was 1.89 (95% CI: 1.5–2.4, P = 2.2 × 10−8) in postmenopausal women. In the NBC, this relative risk in postmenopausal women was 1.81 (95% CI: 1.3–2.6, P = 7.6 × 10−4), which increased to 1.83 (95% CI: 1.4–2.3, P = 9.5 × 10−7) when a history of proliferative breast disease was included in the model. Conclusions: The model combines genotypic and phenotypic factors involved in carcinogenic estrogen metabolite production and cumulative estrogen exposure to predict breast cancer risk. Impact: The estrogen carcinogenesis–based model has the potential to provide personalized risk estimates. Cancer Epidemiol Biomarkers Prev; 20(7); 1502–15. ©2011 AACR.</jats:p

Combined effect of CCND1 and COMT polymorphisms and increased breast cancer risk

<p>Abstract</p> <p>Background</p> <p>Estrogens are crucial tumorigenic hormones, which impact the cell growth and proliferation during breast cancer development. Estrogens are metabolized by a series of enzymes including COMT, which converts catechol estrogens into biologically non-hazardous methoxyestrogens. Several studies have also shown the relationship between estrogen and cell cycle progression through activation of CCND1 transcription.</p> <p>Methods</p> <p>In this study, we have investigated the independent and the combined effects of commonly occurring CCND1 (Pro241Pro, A870G) and COMT (Met108/158Val) polymorphisms to breast cancer risk in two independent Caucasian populations from Ontario (1228 breast cancer cases and 719 population controls) and Finland (728 breast cancer cases and 687 population controls). Both COMT and CCND1 polymorphisms have been previously shown to impact on the enzymatic activity of the coded proteins.</p> <p>Results</p> <p>Here, we have shown that the high enzymatic activity genotype of CCND1^High(AA) was associated with increased breast cancer risk in both the Ontario [OR: 1.3, 95%CI (1.0–1.69)] and the Finland sample [OR: 1.4, 95%CI (1.01–1.84)]. The heterozygous COMT^Medium(MetVal) and the high enzymatic activity of COMT^High(ValVal) genotype was also associated with breast cancer risk in Ontario cases, [OR: 1.3, 95%CI (1.07–1.68)] and [OR: 1.4, 95%CI (1.07–1.81)], respectively. However, there was neither a statistically significant association nor increased trend of breast cancer risk with COMT^High(ValVal) genotypes in the Finland cases [OR: 1.0, 95%CI (0.73–1.39)]. In the combined analysis, the higher activity alleles of the COMT and CCND1 is associated with increased breast cancer risk in both Ontario [OR: <b>2.22</b>, 95%CI (1.49–3.28)] and Finland [OR: <b>1.73</b>, 95%CI (1.08–2.78)] populations studied. The trend test was statistically significant in both the Ontario and Finland populations across the genotypes associated with increasing enzymatic activity.</p> <p>Conclusion</p> <p>Using two independent Caucasian populations, we have shown a stronger combined effect of the two commonly occurring CCND1 and COMT genotypes in the context of breast cancer predisposition.</p

Metabolic inactivation of estrogens in breast tissue by UDP-glucuronosyltransferase enzymes: an overview

The breast tissue is the site of major metabolic conversions of estradiol (E(2)) mediated by specific cytochromes P450 hydroxylations and methylation by catechol-O-methytransferase. In addition to E(2 )itself, recent findings highlight the significance of 4-hydroxylated estrogen metabolites as chemical mediators and their link to breast cancer development and progression, whereas, in opposition, 2-methoxylated estrogens appear to be protective. Recent data also indicate that breast tissue possesses enzymatic machinery to inactivate and eliminate E(2 )and its oxidized and methoxylated metabolites through conjugation catalyzed by UDP-glucuronosyltransferases (UGTs), which involves the covalent addition of glucuronic acid. In opposition to other metabolic pathways of estrogen, the UGT-mediated process leads to the formation of glucuronides that are devoid of biologic activity and are readily excreted from the tissue into the circulation. This review addresses the most recent findings on the identification of UGT enzymes that are responsible for the glucuronidation of E(2 )and its metabolites, and evidence regarding their potential role in breast cancer

Is there a practical alternative to therapeutic drug monitoring in therapy with tricyclic antidepressants?

Abstract Optimization of tricyclic antidepressant (TCA) therapy by dosage adjustments made in response to inappropriate concentrations in plasma or side effects can be extremely slow owing to the long half-lives of these drugs. I examine the practicality of alternative methods of arriving quickly and reliably at an adequate starting dosage. The clearance of a single test dose from plasma has been used to select individualized dosages before commencing therapy, but this takes several days and requires computer-assisted calculation of clearance. A simpler technique is to measure the concentration in a single timed plasma sample as an index of metabolism, and to infer the required dosage directly from a nomogram. Ideally, the nomograms should be interchangeable between patient populations and independent of the analytical method used, and the drug must have linear kinetics. Furthermore, TCAs are metabolized by common routes--demethylation and hydroxylation--so one might apply a single tolerance test for the entire class of drugs. Hydroxylation of TCAs can also be correlated with that of debrisoquine. The debrisoquine clearance test is non-invasive, faster, and analytically less demanding than TCA measurements. In the absence of rigid therapeutic ranges, tests that identify abnormally slow metabolizers may well be invaluable in preventing iatrogenic poisoning. Despite the usefulness of these methods in establishing effective initial dosages, their continued success depends upon good compliance, the maintenance of the patient's concurrent drug therapy, and a stable physical condition. In the non-ideal world, therefore, TDM cannot be dispensed with, but must be seen as an essential part of effective TCA treatment, based ultimately of course on sound clinical judgement.</jats:p

Liquid-chromatographic measurement of nitrazepam in plasma.

Abstract In this simple and rapid "high-performance" liquid-chromatographic method for determining nitrazepam in plasma, serum, or whole blood, the sample at pH 7.4 is extracted into diethyl ether with an internal standard (prazepam), chromatographed, and detected at 280 nm with a fixed-wavelength ultraviolet detector. A specimen, together with standards and a quality control, can be analyzed in duplicate within 90 min. The limit of sensitivity is 5 micrograms/L (nitrazepam and 7-acetamidonitrazepam) and 50 micrograms/L (7-aminonitrazepam), and no interferents have been found. This method has the advantages of a small sample requirement and complete resolution of nitrazepam and the above-mentioned major metabolites. We have used this method for analysis of therapeutic and overdose concentrations of nitrazepam, and to investigate the stability of the drug in blood.</jats:p