Licochalcone A and isoliquiritigenin from Licorice species differentially modulate P450 1B1-mediated estrogen metabolism

The risk of breast cancer increases with cumulative exposure to estrogens. Estrogens are metabolized to genotoxic metabolites by P450 1B1, which is up-regulated through inflammation and activation of the aryl hydrocarbon receptor (AhR). Accordingly, cytokine-induced P450 1B1 mRNA levels were inhibited by either a nuclear factor-kappaB (NF-κB) inhibitor or an AhR antagonist in breast cells. Extracts of three pharmacopoeial licorice species, Glycyrrhiza glabra (GG), G. inflata (GI), and G. uralensis (GU), and their constituents were tested to determine their effects on inflammation and P450 1B1-mediated estrogen metabolism. GI, which specifically contains Licochalcone A (LicA) and has the highest levels of isoliquiritigenin (LigC) equivalents, inhibited iNOS activity more strongly compared to the other species. GI and LicA reduced P450 1B1 mRNA levels with and without cytokines, yet GG, GU, and LigC with cytokines additively increased its expression. Similarly, in a sensitive LC-MS/MS assay, GG, GU, and LigC increased genotoxic estrogen metabolites, yet GI and LicA reduced their production. LicA inhibited whereas LigC increased P450 1A/1B activity. LicA also inhibited TCDD-induced XRE-luciferase reporter activity, indicating AhR antagonism. Thus, GI and LicA may protect women against estrogen carcinogenesis by inhibiting inflammation and P450 1B1-mediated estrogen oxidative metabolism. Supported by NIH Grants P50 AT000155 and T32 AT007533