The Role of Botanicals and Their AhR-Active Compounds in Estrogen Chemical Carcinogenesis

Botanical dietary supplements (BDS) are increasingly popular and may provide resilience in women. Women’s health BDS were initially evaluated for an ability to influence the estrogen detoxification pathways. Estrogen detoxification involves the 2-catechol metabolism of estrogens by P450 1A1 (CYP1A1), which is transcribed by the aryl hydrocarbon receptor (AhR). AhR, however, may also transcribe P450 1B1 (CYP1B1) which metabolizes estrogens to their 4-catechol form. Upon oxidation, the 4-catechol estrogens form genotoxic quinones. Estrogen may activate the estrogen receptor alpha (ERα) which causes the epigenetic inhibition of CYP1A1, leading to preferential metabolism of estrogens by P450 1B1 and the genotoxic pathway of estrogen metabolism. Certain botanicals and bioactive compounds may reverse epigenetic inhibition of AhR-dependent CYP1A1 transcription, and therefore reverse AhR-ERα crosstalk. Botanical extracts which led to preferential transcription of CYP1A1 over CYP1B1 included H. lupulus (hops), hydrolyzed Epimedium (horny goat weed), and Alaskan R. rosea (rose root). Botanicals with known AhR agonists such as hops, containing 6-prenylnaringenin (6-PN), and T. pratense (red clover), containing formononetin and biochanin A, were further evaluated for their influence on the estrogen detoxification pathway. Red clover was subjected to fractionation to produce fractions rich in their AhR agonists or irilone. Irilone potentiated AhR activity but reduced AhR-dependent transcription. Overall, no red clover fractions increased estrogen detoxification activity. Hops and 6-PN were able degrade ERα through AhR-dependent mechanisms and reverse estrogen induced DNA methyl transferase 1 (DNMT1) inhibition of CYP1A1, leading to preferential metabolism of estrogens to their detoxified form. Based on these promising results for the resilience potential of hops in vitro a standardized clinical hop extract was chosen for an in vivo safety and distribution study. Hop extract was shown to be safe in this short study. Xanthohumol was the most prevalent compound in tissues, but estrogenic 8-prenylaringenin and AhR agonist 6-PN were also present. Overall, the distribution of 6-PN in hormone sensitive tissues and safety of hops speaks to its resilience potential in vivo, but more studies are needed to formulate the resilience profile of hops, even though hop BDS are widely available

Mixed messages in iron oxide-copper-gold systems of the Cloncurry district, Australia: insights from PIXE analysis of halogens and copper in fluid inclusions

Proterozoic rocks of the Cloncurry district in NW Queensland, Australia, are host to giant (tens to hundreds of square kilometers) hydrothermal systems that include (1) barren regional sodic–calcic alteration, (2) granite-hosted hydrothermal complexes with magmatic–hydrothermal transition features, and (3) iron oxide–copper–gold (IOCG) deposits. Fluid inclusion microthermometry and proton-induced X-ray emission (PIXE) show that IOCG deposits and the granite-hosted hydrothermal complexes contain abundant high temperature, ultrasaline, complex multisolid (type 1) inclusions that are less common in the regional sodic–calcic alteration. The latter is characterized by lower salinity three-phase halite-bearing (type 2) and two-phase (type 3) aqueous inclusions. Copper contents of the type 1 inclusions (>300 ppm) is higher than in type 2 and 3 inclusions (<300 ppm), and the highest copper concentrations (>1,000 ppm) are found both in the granite-hosted systems and in inclusions with Br/Cl ratios that are consistent with a magmatic source. The Br/Cl ratios of the inclusions with lower Cu contents are consistent with an evaporite-related origin. Wide ranges in salinity and homogenization temperatures for fluid inclusions in IOCG deposits and evidence for multiple fluid sources, as suggested by halogen ratios, indicate fluid mixing as an important process in IOCG genesis. The data support both leaching of Cu by voluminous nonmagmatic fluids from crustal rocks, as well as the direct exsolution of Cu-rich fluids from magmas. However, larger IOCG deposits may form from magmatic-derived fluids based on their higher Cu content