Induction of NAD(P)H:Quinone Oxidoreductase 1 (NQO1) by Glycyrrhiza Species Used for Women’s Health: Differential Effects of the Michael Acceptors Isoliquiritigenin and Licochalcone A

Abstract

For the alleviation of menopausal symptoms, women frequently turn to botanical dietary supplements, such as licorice and hops. In addition to estrogenic properties, these botanicals could also have chemopreventive effects. We have previously shown that hops and its Michael acceptor xanthohumol (XH) induced the chemoprevention enzyme, NAD(P)H:quinone oxidoreductase 1 (NQO1), in vitro and in vivo. Licorice species could also induce NQO1, as they contain the Michael acceptors isoliquiritigenin (LigC) found in Glycyrrhiza glabra (GG), G. uralensis (GU), and G. inflata (GI) and licochalcone A (LicA) which is only found in GI. These licorice species and hops induced NQO1 activity in murine hepatoma (Hepa1c1c7) cells; hops >> GI > GG ≅ GU. Similar to the known chemopreventive compounds curcumin (turmeric), sulforaphane (broccoli), and XH, LigC and LicA were active dose-dependently; sulforaphane >> XH > LigC > LicA ≅ curcumin >> LigF. Induction of the antioxidant response element-luciferase in human hepatoma (Hep-G2-ARE-C8) cells suggested involvement of the Keap1-Nrf2 pathway. GG, GU, and LigC also induced NQO1 in non-tumorigenic breast epithelial MCF-10A cells. In female Sprague-Dawley rats treated with GG and GU, LigC and LigF were detected in the liver and mammary gland. GG weakly enhanced NQO1 activity in the mammary tissue but not in the liver. Treatment with LigC alone did not induce NQO1 in vivo most likely due to its conversion to LigF, extensive metabolism, and its low bioavailability in vivo. These data show the chemopreventive potential of licorice species in vitro could be due to LigC and LicA and emphasize the importance of chemical and biological standardization of botanicals used as dietary supplements. Although the in vivo effects in the rat model after four day treatment are minimal, it must be emphasized that menopausal women take these supplements for extended periods of time and long-term beneficial effects are quite possible.

Cytochrome P450 inhibition by three licorice species and fourteen licorice constituents

“…Licorice powders were botanically identified through DNA-based identification, macroscopic and microscopic analyses, and comparison with voucher specimens at the Field Museum of Natural History (Chicago, IL) as well as DNA barcoding as described previously (Simmler et al , 2015a). The root powders from each species were extracted by maceration at room temperature with a solvent mixture consisting of ethanol (200 USP proof), isopropanol and water (90:5:5, v/v/v) and a plant powder/volume of solvent ratio of 1:15 (Hajirahimkhan et al , 2015). The quantitative analysis of 14 licorice constituents in the extracts was carried out using a UHPLC-MS/MS assay as described previously (Li, et al ., 2016).…”

Botanicals and Their Bioactive Phytochemicals for Women’s Health

“…G. uralensis was reported to induce Nrf2-mediated genes in hepatoma cells and animal tissues ( Wu et al, 2011 ). In a comparative analysis, G. glabra, G. uralensis , and G. inflata induced NQO1 dose dependently in murine hepatoma (hepa1c1c7) and breast epithelial (MCF-10A) cells ( Hajirahimkhan et al, 2015 ). However, when G. glabra and G. uralensis were administered orally to female rats, no NQO1 induction was observed in liver, whereas G. glabra had a slight but significant NQO1 induction in mammary tissue ( Hajirahimkhan et al, 2015 ).…”

“…For example, liquiritigenin ( Fig. 27 ) from licorice and curcumin from turmeric form multiple glucuronides ( Ganesan et al, 2015 ; Hajirahimkhan et al, 2015 ). In the case of curcumin, efforts are underway to improve its bioavailability and therefore enhance its clinical efficacy ( Ganesan et al, 2015 ).…”

Isolation and structural characterization of dihydrobenzofuran congeners of licochalcone A

“…In light of the diverse biological properties attributed to these retrochalcones [34], notably LicA and its derivatives [35][36][37][38][39], the photoisomerization studies conducted under bio-assays conditions [30], deserves consideration, as the variable ratio of cis and trans isomers may exert an effect on the biological response over time.…”