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.