Modulation of Estrogen Metabolism by Hops Extracts and Bioactive Compounds as Analyzed by LC-MS-MS
Snelten, Courtney S.
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The oxidative metabolism of estrogens into estrogen quinones that damage DNA, contributes to the carcinogenicity of estrogens. In order to circumvent using hormone replacement therapy, many women in the United States use botanical dietary supplements as a means to alleviate menopausal symptoms and avoid associated cancer risks. Little is known about the ability of these botanicals to alter estrogen metabolism leading to breast cancer. The hypothesis of this thesis is that botanicals used by women for menopausal symptom relief have beneficial chemopreventive activities by reducing exposure to genotoxic estrogen metabolites and improving overall wellness by reducing the negative effects of estrogen. Our previous studies have shown that hops (Humulus lupulus), a component of popular European botanical dietary supplements used for relief of menopausal symptoms, inhibits estradiol metabolism to the 2- and 4-methoxyestrone (MeOE1) metabolites. Utilizing an optimized LC-MS-MS assay I investigated 3 major constituents within hops ability to alter estrogen metabolism and the CYP1B1 and CYP1A1 activity and mRNA expression which are responsible for estrogen metabolite oxidation. The hypothesis was supported by the observation that five hops extracts altered estrogen metabolism and the one with the highest amount of isoxanthohumol and 8-prenylnaringenin increased the benign metabolite marker 2-methoxyestrone while simultaneously decreasing the genotoxic metabolite marker 4-methoxyestrone. While xanthohumol did not alter estrogen metabolism, 8-prenylnaringenin and isoxanthohumol altered the amount of the genotoxic metabolite 4-methoxyestrone although in opposite manners. 8-prenylnaringenin treatment increased the genotoxic metabolite 4-methoxyestrone by increasing the mRNA for the enzyme responsible for its production (CYP1B1). On the other hand, isoxanthohumol treatment decreased the genotoxic metabolite 4-methoxyestrone by directly inhibiting the enzyme. The data suggests that hops extracts, specifically those with high levels of isoxanthohumol, have beneficial chemopreventive activities by reducing the genotoxic pathway of estrogen metabolism and could potentially improve overall wellness by reducing the negative effects of estrogen.