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Timothy D. Veenstra - One of the best experts on this subject based on the ideXlab platform.
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Estrogen Metabolism and Risk of Breast Cancer in Postmenopausal Women
2016Co-Authors: Barbara J. Fuhrman, Mitchell H. Gail, Jennifer Boyd-morin, Laura Y. Sue, Saundra S. Buys, Claudine Isaacs, Larry K. Keefer, Timothy D. Veenstra, Christine D. BergAbstract:Prospective studies of postmenopausal women have consistently demonstrated that higher levels of circulating estradiol, estrone, and estrone sulfate are associated with an increased risk of breast cancer (1). These associations have long been thought to result from mitogenic effects mediated by the Estrogen receptor. It has been hypothesized that Estrogen Metabolism may also play a role in breast cancer etiology. The parent Estrogens (ie, estrone and estradiol) can be irreversibly hydroxylated at the C-2, C-4, or C-16 positions of the steroid ring (Figure 1) to produce Estrogen metabolites that differ in their bioavailability to breast tissues (3) and activation of Estrogen receptors (4). In addition, catechol Estrogens, which are formed by 2- and 4-hydroxylation, can be oxidized to form mutagenic quinones (5–7); this process is prevented by methylation of one of the adjacent hydroxyl groups (8). Estrogens and Estrogen metabolites can also be conjugated via sulfation or glucuronidation, each of which modifies bioavail-ability (9). Laboratory and clinical studies have suggested several hypotheses about how Estrogen Metabolism might influence the risk of breast cancer (10–13). However, robust tests of thes
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association of active and sedentary behaviors with postmenopausal Estrogen Metabolism
Medicine and Science in Sports and Exercise, 2016Co-Authors: Cher M Dallal, Charles E. Matthews, Timothy D. Veenstra, Louise A Brinton, Ruth M Pfeiffer, Terryl J Hartman, Jolanta Lissowska, Roni T Falk, Montserrat Garciaclosas, Gretchen L GierachAbstract:Purpose Physical activity may reduce endogenous Estrogens, but few studies have assessed effects on Estrogen Metabolism and none have evaluated sedentary behavior in relation to Estrogen Metabolism. We assessed relationships between accelerometer-measured physical activity and sedentary behavior and 15 urinary Estrogens and Estrogen metabolites (EM) among postmenopausal controls from a population-based breast cancer case-control study conducted in Poland (2000-2003). Methods Postmenopausal women (N = 542) were ages 40 to 72 yr and not currently using hormone therapy. Accelerometers, worn for 7 d, were used to derive measures of average activity (counts per day) and sedentary behavior (<100 counts per minute per day). Estrogen metabolites were measured in 12-h urine samples using liquid chromatography-tandem mass spectrometry. Estrogen metabolites were analyzed individually, in metabolic pathways (C-2, -4, or -16), and as ratios relative to parent Estrogens. Geometric means of Estrogen metabolites by tertiles of accelerometer-measures, adjusted for age and body mass, were computed using linear models. Results High activity was associated with lower levels of estrone and estradiol (P trend = 0.01), whereas increased sedentary time was positively associated with these parent Estrogens (P trend = 0.04). Inverse associations were observed between high activity and 2-methoxyestradiol, 4-methoxyestradiol, 17-epiestriol, and 16-epiestriol (P trend = 0.03). Sedentary time was positively associated with methylated catechols in the 2- and 4-hydroxylation pathways (P trend <= 0.04). Women in the highest tertile of activity had increased hydroxylation at the C-2, -4, and -16 sites relative to parent Estrogens (P trend <= 0.02), whereas increased sedentary time was associated with a lower 16-pathway/parent Estrogen ratio (P trend = 0.01). Conclusions Higher activity was associated with lower urinary Estrogens, possibly through increased Estrogen hydroxylation and subsequent Metabolism, whereas sedentary behavior may reduce Metabolism.
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Estrogen Metabolism within the lung and its modulation by tobacco smoke
Carcinogenesis, 2013Co-Authors: Jing Peng, Timothy D. Veenstra, Brian E Mace, Lisa Vanderveer, Laura Workman, Michael Slifker, Patrick Sullivan, Margie L ClapperAbstract:Although Estrogen and the enzymes responsible for its Metabolism have been detected within the lung, the ability of this tissue to metabolize Estrogen has not been demonstrated previously. The goal of this study was to characterize the profile of Estrogen metabolites within the murine lung and to determine the effect of tobacco smoke exposure on metabolite levels. Use of liquid chromatography-tandem mass spectrometry led to the detection of three Estrogens (E1, E2 and E3) and five Estrogen metabolites (2-OHE1, 4-OHE1, 4-OHE2, 2-OMeE1 and 2-OMeE2) within the perfused lung, with 4-OHE1 being the most abundant species. Levels of 4-OHEs, carcinogenic derivatives produced primarily by cytochrome P450 1B1 (Cyp1b1), were 2-fold higher in females than males. Deletion of Cyp1b1 in females led to a dramatic reduction (21-fold) in 4-OHEs, whereas levels of 2-OHE1 and the putative protective Estrogen metabolite 2-OMeE2 were increased (2.4- and 5.0-fold, respectively) (P = 0.01). Similar quantitative differences in Estrogen metabolite levels were observed between Cyp1b1 null and wild-type males. Exposure of female mice to tobacco smoke for 8 weeks (2h per day, 5 days per week) increased the levels of 4-OHE1 (4-fold) and 2-OHE2 (2-fold) within the lung while reducing the total concentration of 2-OMeEs to 70% of those of unexposed controls. These data suggest that tobacco smoke accelerates the production of 4-OHEs within the lung; carcinogenic metabolites that could potentially contribute to lung tumor development. Thus, inhibition of CYP1B1 may represent a promising strategy for the prevention and treatment of lung cancer.
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Estrogen Metabolism and risk of breast cancer in postmenopausal women
Journal of the National Cancer Institute, 2012Co-Authors: Barbara J. Fuhrman, Mitchell H. Gail, Laura Y. Sue, Saundra S. Buys, Claudine Isaacs, Larry K. Keefer, Timothy D. Veenstra, Catherine Schairer, Jennifer Boydmorin, Christine D. BergAbstract:Results Nearly all Estrogens, Estrogen metabolites, and metabolic pathway groups were associated with an increased risk of breast cancer; the serum concentration of unconjugated estradiol was strongly associated with the risk of breast cancer (HR = 2.07, 95% confidence interval [CI] = 1.19 to 3.62). No Estrogen, Estrogen metabolite, or metabolic pathway group remained statistically significantly associated with the risk of breast cancer after adjusting for unconjugated estradiol. The ratio of the 2-hydroxylation pathway to parent Estrogens (HR = 0.66, 95% CI = 0.51 to 0.87) and the ratio of 4-hydroxylation pathway catechols to 4-hydroxylation pathway methylated catechols (HR = 1.34, 95% CI = 1.04 to 1.72) were statistically significantly associated with the risk of breast cancer and remained so after adjustment for unconjugated estradiol. Conclusions More extensive 2-hydroxylation of parent Estrogens is associated with lower risk, and less extensive methylation of potentially genotoxic 4-hydroxylation pathway catechols is associated with higher risk of postmenopausal breast cancer.
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effect of tumor necrosis factor α on Estrogen Metabolism and endometrial cells potential physiological and pathological relevance
The Journal of Clinical Endocrinology and Metabolism, 2009Co-Authors: Salama A Salama, Timothy D. Veenstra, Marwa Kamel, Concepcion Diazarrastia, Sana M Salih, Shaleen K Botting, Raj KumarAbstract:Context: Estrogen and its metabolites play a critical role in the pathophysiology of the endometrium. The bioavailability of Estrogen and Estrogen metabolites in endometrial tissues depends on the expression of enzymes involved in Estrogen biosynthesis and Metabolism. Substantial evidence indicates that Estrogen-dependent endometrial disorders are also associated with proinflammatory milieu. However, the mechanism whereby inflammation contributes to these conditions is not known. Objective: The objective of the study was to investigate the effect of TNF-α on Estrogen Metabolism and the expression of Estrogen-metabolizing genes in human endometrial glandular epithelial cells (EM1). Design: EM1 were treated with 17β-estradiol (E2) with or without TNF-α. Capillary liquid chromatography-tandem mass spectrometry analysis was used for quantitative measurement of Estrogens and Estrogen metabolites. Western blot analysis, reporter gene assay, and real-time RT-PCR were used to assess the expression of Estrogen-metabolizing genes. Results: TNF-α treatment significantly increased the level of total Estrogen and Estrogen metabolites and significantly increased the rate of conversion of estrone (E1) into E2. TNF-α also enhanced the oxidative Metabolism of Estrogen into catecholEstrogens with concomitant inhibition of their conversion into methoxyEstrogens. Gene expression analysis revealed that TNF-α induced the expression of genes involved in E2 biosynthesis (steroidogenic factor-1 and aromatase) and activation (17β- hydroxysteroid dehydrogenase type 1 and cytochrome P-450, 1B1) with simultaneous repression of genes involved in Estrogen inactivation (17β-hydroxysteroid dehydrogenase type 2; catechol O-methyltransferase; and nicotinamide adenine dinucleotide phosphate-quinone oxidoreductase 1). Conclusion: TNF-α increases the local Estrogen biosynthesis in human endometrial glandular cells and directs Estrogen Metabolism into more hormonally active and carcinogenic metabolites. These effects may impact many physiological and pathological processes that occur within the endometrium.
Mindy S. Kurzer - One of the best experts on this subject based on the ideXlab platform.
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Estrogen Metabolism and breast cancer
Cancer Letters, 2015Co-Authors: Hamed Samavat, Mindy S. KurzerAbstract:There is currently accumulating evidence that endogenous Estrogens play a critical role in the development of breast cancer. Estrogens and their metabolites have been studied in both pre- and postmenopausal women with more consistent results shown in the latter population, in part because of large hormonal variations during the menstrual cycle and far fewer studies having been performed in premenopausal women. In this review we describe in detail Estrogen Metabolism and associated genetic variations, and provide a critical review of the current literature regarding the role of Estrogens and their metabolites in breast cancer risk.
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the effects of aerobic exercise on Estrogen Metabolism in healthy premenopausal women
Cancer Epidemiology Biomarkers & Prevention, 2013Co-Authors: Alma J Smith, William Thomas, William R Phipps, Kathryn H Schmitz, Mindy S. KurzerAbstract:Background: It is well accepted that exercise can decrease breast cancer risk. Limited clinical evidence suggests that this risk could be mediated through changes in Estrogen Metabolism in premenopausal women. Our objective was to investigate the effects of exercise on premenopausal Estrogen Metabolism pertinent to breast cancer risk. Methods: Sedentary, healthy, young eumenorrheic women were randomized into an intervention of 30 minutes of moderate-to-vigorous aerobic exercise five times a week for approximately 16 weeks ( n = 212), or into a usual-lifestyle sedentary control group ( n = 179). Urinary levels of Estrogens [estrone [E1], estradiol, and estriol] and nine Estrogen metabolites were measured at baseline and at study end by liquid chromatography/tandem mass spectrometry. The ratios of 2-hydroxyestrone to 16α-hydroxyestrone (2-OHE1/16α-OHE1) and 2-OHE1 to 4-hydroxyestrone (2- OHE1/4-OHE1) were also calculated. Results: The exercise intervention resulted in significant increases in aerobic fitness and lean body mass and a significant decrease in percent body fat. For exercisers who completed the study ( n = 165), 2-OHE1/16α-OHE1 increased significantly ( P = 0.043), whereas E1 decreased significantly ( P = 0.030) in control participants ( n = 153). The change from baseline in 2-OHE1/16α-OHE1 was significantly different between groups ( P = 0.045), even after adjustment for baseline values. Conclusions: The exercise intervention resulted in a significant increase in the 2-OHE1/16α-OHE1 ratio but no differences in other Estrogen metabolites or ratios. Impact: Our results suggest that changes in premenopausal Estrogen Metabolism may be a mechanism by which increased physical activity lowers breast cancer risk. Cancer Epidemiol Biomarkers Prev; 22(5); 756–64. ©2013 AACR . This article is featured in Highlights of This Issue, [p. 745][1] [1]: /lookup/volpage/22/745?iss=5
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soy protein isolate increases urinary Estrogens and the ratio of 2 16alpha hydroxyestrone in men at high risk of prostate cancer
Journal of Nutrition, 2007Co-Authors: Jill M Hamiltonreeves, Salome A. Rebello, William Thomas, Joel W. Slaton, Mindy S. KurzerAbstract:Specific Estrogen metabolites may initiate and promote hormone-related cancers. In epidemiological studies, significantly lower excretion of urinary estradiol (E2) and lower ratio of urinary 2-hydroxy Estrogens to 16alpha-hydroxyestrone (2:16 OH-E1) have been reported in prostate cancer cases compared to controls. Although soy supplementation has been shown to increase the ratio 2:16 OH-E1 in women, no studies to our knowledge have investigated the effects of soy supplementation on Estrogen Metabolism in men. The objective of this randomized controlled trial was to determine the effects of soy protein isolate consumption on Estrogen Metabolism in men at high risk for developing advanced prostate cancer. Fifty-eight men supplemented their habitual diets with 1 of 3 protein isolates: 1) isoflavone-rich soy protein isolate (SPI+) (107 mg isoflavones/d); 2) alcohol-washed soy protein isolate (SPI-) (<6 mg isoflavones/d); or 3) milk protein isolate (MPI), each providing 40 g protein/d. At 0, 3, and 6 mo of supplementation, the urinary Estrogen metabolite profile was measured by GC-MS. Both soy groups had higher E2 excretion than the MPI group at 3 and 6 mo. After 6 mo of supplementation, the SPI+ group had a significantly higher urinary 2:16 OH-E1 ratio than the MPI group. Increased urinary E2 excretion and 2:16 OH-E1 ratio in men consuming soy protein isolate are consistent with studies in postmenopausal women and suggest that soy consumption may be beneficial in men at high risk of progressing to advanced prostate cancer as a result of effects on endogenous Estrogen Metabolism.
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soy consumption alters endogenous Estrogen Metabolism in postmenopausal women
Cancer Epidemiology Biomarkers & Prevention, 2000Co-Authors: Alison M Duncan, Kerry E Wangen, Mindy S. KurzerAbstract:Isoflavones are soy phytoEstrogens that have been suggested to be anticarcinogenic. Our previous study in premenopausal women suggested that the mechanisms by which isoflavones exert cancer-preventive effects may involve modulation of Estrogen Metabolism away from production of potentially carcinogenic metabolites [16alpha-(OH) estrone, 4-(OH) estrone, and 4-(OH) estradiol] (X. Xu et al., Cancer Epidemiol. Biomark. Prev., 7: 1101-1108, 1998). To further evaluate this hypothesis, a randomized, cross-over soy isoflavone feeding study was performed in 18 healthy postmenopausal women. The study consisted of three diet periods, each separated by a washout of approximately 3 weeks. Each diet period lasted for 93 days, during which subjects consumed their habitual diets supplemented with soy protein isolate providing 0.1 (control), 1, or 2 mg isoflavones/kg body weight/day (7.1 +/- 1.1, 65 +/- 11, or 132 +/- 22 mg/day). A 72-h urine sample was collected 3 days before the study (baseline) and days 91-93 of each diet period. Urine samples were analyzed for 10 phytoEstrogens and 15 endogenous Estrogens and their metabolites by a capillary gas chromatography-mass spectrometry method. Compared with the soy-free baseline and very low isoflavone control diet, consumption of 65 mg isoflavones increased the urinary 2/16alpha-(OH) estrone ratio, and consumption of 65 or 132 mg isoflavones decreased excretion of 4-(OH) estrone. When compared with baseline values, consumption of all three soy diets increased the ratio of 2/4-(OH) Estrogens and decreased the ratio of genotoxic: total Estrogens. These data suggest that both isoflavones and other soy constituents may exert cancer-preventive effects in postmenopausal women by altering Estrogen Metabolism away from genotoxic metabolites toward inactive metabolites.
Judy L Bolton - One of the best experts on this subject based on the ideXlab platform.
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differential effects of glycyrrhiza species on genotoxic Estrogen Metabolism licochalcone a downregulates p450 1b1 whereas isoliquiritigenin stimulates it
Chemical Research in Toxicology, 2015Co-Authors: Tareisha L Dunlap, Shuai Wang, Charlotte Simmler, Shaonong Chen, Guido F Pauli, Birgit M Dietz, Judy L BoltonAbstract:Estrogen chemical carcinogenesis involves 4-hydroxylation of estrone/estradiol (E1/E2) by P450 1B1, generating catechol and quinone genotoxic metabolites that cause DNA mutations and initiate/promote breast cancer. Inflammation enhances this effect by upregulating P450 1B1. The present study tested the three authenticated medicinal species of licorice [Glycyrrhiza glabra (GG), G. uralensis (GU), and G. inflata (GI)] used by women as dietary supplements for their anti-inflammatory activities and their ability to modulate Estrogen Metabolism. The pure compounds, liquiritigenin (LigF), its chalcone isomer isoliquiritigenin (LigC), and the GI-specific licochalcone A (LicA) were also tested. The licorice extracts and compounds were evaluated for anti-inflammatory activity by measuring inhibition of iNOS activity in macrophage cells: GI ≫ GG > GU and LigC ≅ LicA ≫ LigF. The Michael acceptor chalcone, LicA, is likely responsible for the anti-inflammatory activity of GI. A sensitive LC-MS/MS assay was employed to...
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differential effects of glycyrrhiza species on genotoxic Estrogen Metabolism licochalcone a downregulates p450 1b1 whereas isoliquiritigenin stimulates it
Chemical Research in Toxicology, 2015Co-Authors: Tareisha L Dunlap, Shuai Wang, Charlotte Simmler, Shaonong Chen, Guido F Pauli, Birgit M Dietz, Judy L BoltonAbstract:Estrogen chemical carcinogenesis involves 4-hydroxylation of estrone/estradiol (E1/E2) by P450 1B1, generating catechol and quinone genotoxic metabolites that cause DNA mutations and initiate/promote breast cancer. Inflammation enhances this effect by upregulating P450 1B1. The present study tested the three authenticated medicinal species of licorice [Glycyrrhiza glabra (GG), G. uralensis (GU), and G. inflata (GI)] used by women as dietary supplements for their anti-inflammatory activities and their ability to modulate Estrogen Metabolism. The pure compounds, liquiritigenin (LigF), its chalcone isomer isoliquiritigenin (LigC), and the GI-specific licochalcone A (LicA) were also tested. The licorice extracts and compounds were evaluated for anti-inflammatory activity by measuring inhibition of iNOS activity in macrophage cells: GI ≫ GG > GU and LigC ≅ LicA ≫ LigF. The Michael acceptor chalcone, LicA, is likely responsible for the anti-inflammatory activity of GI. A sensitive LC-MS/MS assay was employed to quantify Estrogen Metabolism by measuring 2-MeOE1 as nontoxic and 4-MeOE1 as genotoxic biomarkers in the nontumorigenic human mammary epithelial cell line, MCF-10A. GG, GU, and LigC increased 4-MeOE1, whereas GI and LicA inhibited 2- and 4-MeOE1 levels. GG, GU (5 μg/mL), and LigC (1 μM) also enhanced P450 1B1 expression and activities, which was further increased by inflammatory cytokines (TNF-α and IFN-γ). LicA (1, 10 μM) decreased cytokine- and TCDD-induced P450 1B1 gene expression and TCDD-induced xenobiotic response element luciferase reporter (IC50 = 12.3 μM), suggesting an antagonistic effect on the aryl hydrocarbon receptor, which regulates P450 1B1. Similarly, GI (5 μg/mL) reduced cytokine- and TCDD-induced P450 1B1 gene expression. Collectively, these data suggest that, of the three licorice species that are used in botanical supplements, GI represents the most promising chemopreventive licorice extract for women's health. Additionally, the differential effects of the Glycyrrhiza species on Estrogen Metabolism emphasize the importance of standardization of botanical supplements to species-specific bioactive compounds.
T A Wang - One of the best experts on this subject based on the ideXlab platform.
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effects of docosahexaenoic acid supplementation on blood lipids Estrogen Metabolism and in vivo oxidative stress in postmenopausal vegetarian women
European Journal of Clinical Nutrition, 2006Co-Authors: T F Wang, H J Jou, T A WangAbstract:Effects of docosahexaenoic acid supplementation on blood lipids, Estrogen Metabolism, and in vivo oxidative stress in postmenopausal vegetarian women
Fritz F Parl - One of the best experts on this subject based on the ideXlab platform.
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Estrogen Exposure, Metabolism, and Enzyme Variants in a Model for Breast Cancer Risk Prediction
2016Co-Authors: Fritz F Parl, Kathleen M. Egan, Philip S CrookeAbstract:Abstract: Estrogen is a well-known risk factor for breast cancer. Current models of breast cancer risk prediction are based on cumulative Estrogen exposure but do not directly refl ect mammary Estrogen Metabolism or address genetic variability between women in exposure to carcinogenic Estrogen metabolites. We are proposing a mathematical model that forecasts breast cancer risk for a woman based on three factors: (1) estimated Estrogen exposure, (2) kinetic analysis of the oxidative Estrogen Metabolism pathway in the breast, and (3) enzyme genotypes responsible for inherited differences in the production of carcinogenic metabolites. The model incorporates the main components of mammary Estrogen Metabolism, i.e. the con-version of 17β-estradiol (E2) by the phase I and II enzymes cytochrome P450 (CYP) 1A1 and 1B1, catechol-O-methyltransferase (COMT), and glutathione S-transferase P1 (GSTP1) into reactive metabolites, including catechol Estrogens and Estrogen quinones, such as E2-3,4-Q which can damage DNA. Each of the four genes is genotyped and the SNP data used to derive the haplotype confi guration for each subject. The model then utilizes the kinetic and genotypic data to calculate the amount of E2-3,4-Q carcinogen as ultimate risk factor for each woman. The proposed model extends existing models by combining the traditional “phenotypic ” measures of Estrogen exposure with genotypic data associated with the metabolic fate of E2 as determined by critical phase I and II enzymes. Instead of providing a general risk estimate our model would predict the ris
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Estrogen Metabolism and breast cancer a risk model
Annals of the New York Academy of Sciences, 2009Co-Authors: Fritz F Parl, Nady Roodi, Sheila Dawling, Philip S CrookeAbstract:Oxidative metabolites of Estrogens have been implicated in the development of breast cancer, yet relatively little is known about the Metabolism of Estrogens in the normal breast. We developed an experimental in vitro model of mammary Estrogen Metabolism in which we combined purified, recombinant phase I enzymes CYP1A1 and CYP1B1 with the phase II enzymes COMT and GSTP1 to determine how 17beta-estradiol (E(2)) is metabolized. We employed both gas and liquid chromatography with mass spectrometry to measure the parent hormone E(2) as well as eight metabolites, that is, the catechol Estrogens, methoxyEstrogens, and Estrogen-GSH conjugates. We used these experimental data to develop an in silico model, which allowed the kinetic simulation of converting E(2) into eight metabolites. The simulations showed excellent agreement with experimental results and provided a quantitative assessment of the metabolic interactions. Using rate constants of genetic variants of CYP1A1, CYP1B1, and COMT, the model further allowed examination of the kinetic impact of enzyme polymorphisms on the entire metabolic pathway, including the identification of those haplotypes producing the largest amounts of catechols and quinones. Application of the model to a breast cancer case-control population defined the Estrogen quinone E(2)-3,4-Q as a potential risk factor and identified a subset of women with an increased risk of breast cancer based on their enzyme haplotypes and consequent E(2)-3,4-Q production. Our in silico model integrates diverse types of data and offers the exciting opportunity for researchers to combine metabolic and genetic data in assessing Estrogenic exposure in relation to breast cancer risk.
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cytochrome p450 1b1 mediated Estrogen Metabolism results in Estrogen deoxyribonucleoside adduct formation
Cancer Research, 2007Co-Authors: Alexandra R Belous, David L Hachey, Nady Roodi, Sheila Dawling, Fritz F ParlAbstract:The oxidative Metabolism of Estrogens has been implicated in the development of breast cancer; yet, relatively little is known about the mechanism by which Estrogens cause DNA damage and thereby initiate mammary carcinogenesis. To determine how the Metabolism of the parent hormone 17β-estradiol (E2) leads to the formation of DNA adducts, we used the recombinant, purified phase I enzyme, cytochrome P450 1B1 (CYP1B1), which is expressed in breast tissue, to oxidize E2 in the presence of 2′-deoxyguanosine or 2′-deoxyadenosine. We used both gas and liquid chromatography with tandem mass spectrometry to measure E2, the 2- and 4-catechol Estrogens (2-OHE2, 4-OHE2), and the depurinating adducts 4-OHE2-1(α,β)-N7-guanine (4-OHE2-N7-Gua) and 4-OHE2-1(α,β)-N3-adenine (4-OHE2-N3-Ade). CYP1B1 oxidized E2 to the catechol 4-OHE2 and the labile quinone 4-hydroxyestradiol-quinone to produce 4-OHE2-N7-Gua and 4-OHE2-N3-Ade in a time- and concentration-dependent manner. Because the reactive quinones were produced as part of the CYP1B1-mediated oxidation reaction, the adduct formation followed Michaelis-Menten kinetics. Under the conditions of the assay, the 4-OHE2-N7-Gua adduct (Km, 4.6 ± 0.7 μmol/L; kcat, 45 ± 1.6/h) was produced 1.5 times more efficiently than the 4-OHE2-N3-Ade adduct (Km, 4.6 ± 1.0 μmol/L; kcat, 30 ± 1.5/h). The production of adducts was two to three orders of magnitude lower than the 4-OHE2 production. The results present direct proof of CYP1B1-mediated, E2-induced adduct formation and provide the experimental basis for future studies of Estrogen carcinogenesis. [Cancer Res 2007;67(2):812–7]
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in vitro model of mammary Estrogen Metabolism structural and kinetic differences between catechol Estrogens 2 and 4 hydroxyestradiol
Chemical Research in Toxicology, 2004Co-Authors: Sheila Dawling, Nady Roodi, David L Hachey, Fritz F ParlAbstract:Estrogens and their oxidative metabolites, the catechol Estrogens, have been implicated in the development of breast cancer; yet, relatively little is known about Estrogen Metabolism in the breast. To determine how the parent hormone, 17 beta-estradiol (E(2)), is metabolized, we used recombinant, purified phase I enzymes, cytochrome P450 (CYP) 1A1 and 1B1, with the phase II enzymes catechol-O-methyltransferase (COMT) and glutathione S-transferase P1 (GSTP1), all of which are expressed in breast tissue. We employed both gas and liquid chromatography with mass spectrometry to measure E(2), the catechol Estrogens 2-hydroxyestradiol (2-OHE(2)) and 4-hydroxyestradiol (4-OHE(2)), as well as methoxyEstrogens and Estrogen-GSH conjugates. The oxidation of E(2) to 2-OHE(2) and 4-OHE(2) was exclusively regulated by CYP1A1 and 1B1, regardless of the presence or concentration of COMT and GSTP1. COMT generated two products, 2-methoxyestradiol and 2-hydroxy-3-methoxyestradiol, from 2-OHE(2) but only one product, 4-methoxyestradiol, from 4-OHE(2). Similarly, GSTP1 yielded two conjugates, 2-OHE(2)-1-SG and 2-OHE(2)-4-SG, from the corresponding quinone 2-hydroxyestradiol-quinone and one conjugate, 4-OHE(2)-2-SG, from 4-hydroxyestradiol-quinone. Using the experimental data, we developed a multicompartment kinetic model for the oxidative Metabolism of the parent hormone E(2), which revealed significant differences in rate constants for its C-2 and C-4 metabolites. The results demonstrated a tightly regulated interaction of phase I and phase II enzymes, in which the latter decreased the concentration of catechol Estrogens and Estrogen quinones, thereby reducing the potential of these oxidative Estrogen metabolites to induce DNA damage.
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multifactor dimensionality reduction reveals high order interactions among Estrogen Metabolism genes in sporadic breast cancer
American Journal of Human Genetics, 2001Co-Authors: Marylyn D Ritchie, Fritz F Parl, Nady Roodi, Lance W Hahn, Renee L Bailey, William D Dupont, Jason H MooreAbstract:One of the greatest challenges facing human geneticists is the identification and characterization of susceptibility genes for common complex multifactorial human diseases. This challenge is partly due to the limitations of parametric-statistical methods for detection of gene effects that are dependent solely or partially on interactions with other genes and with environmental exposures. We introduce multifactor-dimensionality reduction (MDR) as a method for reducing the dimensionality of multilocus information, to improve the identification of polymorphism combinations associated with disease risk. The MDR method is nonparametric (i.e., no hypothesis about the value of a statistical parameter is made), is model-free (i.e., it assumes no particular inheritance model), and is directly applicable to case-control and discordant-sib-pair studies. Using simulated case-control data, we demonstrate that MDR has reasonable power to identify interactions among two or more loci in relatively small samples. When it was applied to a sporadic breast cancer case-control data set, in the absence of any statistically significant independent main effects, MDR identified a statistically significant high-order interaction among four polymorphisms from three different Estrogen-Metabolism genes. To our knowledge, this is the first report of a four-locus interaction associated with a common complex multifactorial disease.