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Changes in 2-Hydroxyestrone and 16-Hydroxyestrone Metabolism with Flaxseed Consumption: Modification by COMT and CYP1B1 Genotype

¹ Department of Epidemiology, Roswell Park Cancer Institute; Departments of ² Social and Preventive Medicine and ³ Pharmacology and Toxicology, University at Buffalo, Buffalo, New York; ⁴ New York State Department of Health, Western Regional Office, Rochester, New York; ⁵ Department of Environmental and Occupational Health, University of Arkansas for Medical Sciences, Little Rock, Arizona; ⁶ Department of Epidemiology, Italian National Cancer Institute Regina Elena, Rome, Italy; and ⁷ Department of Cancer Epidemiology and Genetics, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia

Requests for reprints: Susan E. McCann, Department of Epidemiology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263. Phone: 716-845-8842; Fax: 716-845-8487. E-mail: susan.mccann{at}roswellpark.org

Consumption of the phytoestrogen lignans, structurally similar to estrogen, has been associated with alterations in gene expression and estrogen metabolism. Furthermore, lignan consumption, subsequent changes in metabolizing enzyme expression, and genetic variability in these enzymes may alter estrogen metabolism and modify disease risk. Therefore, we investigated the effect of flaxseed on hydroxyestrone metabolite excretion by catechol-O-methyltransferase (COMT) and cytochrome P450 1B1 (CYP1B1) genotype. We conducted an intervention among 132 healthy, postmenopausal women, ages 46 to 75 years. Participants consumed 10 g ground flaxseed daily for 7 consecutive days. Blood and urine samples were collected at baseline and after the 7-day intervention. COMT Val¹⁵⁸Met and CYP1B1 Leu⁴³²Val genotypes were determined using PCR-RFLP methods. Urinary 2-hydroxyestrone (2OHE1) and 16-hydroxyestrone (16OHE1) were quantified by ELISA assay. The effect of genotype on intervention-related changes in estrogen metabolites was assessed with the Kruskal-Wallis test. Compared with baseline levels, postintervention levels of urinary 2OHE1 (ng/mg creatinine; mean ± SD, 16.1 ± 10.6 versus 9.3 ± 6.9, postintervention and baseline, respectively; P < 0.01) and 2OHE1/16OHE1 ratios (mean ± SD, 2.73 ± 1.47 versus 1.54 ± 0.75, postintervention and baseline, respectively; P < 0.01) were significantly higher. The change in 2OHE1/16OHE1 increased with increasing numbers of variant alleles for COMT (mean change: Val/Val, 0.90; Val/Met, 1.15; and Met/Met, 1.50; P = 0.17, Kruskal-Wallis) and especially CYP1B1 (mean change: Leu/Leu, 0.89; Leu/Val, 1.32; and Val/Val, 1.51; P = 0.04, Kruskal-Wallis). Our findings suggest that variation in hormone-related genes may modify the effect of dietary lignan exposures on estrogen metabolism. (Cancer Epidemiol Biomarkers Prev 2007;16(2):256–62)