title: Differential regulation of detoxification enzymes in hepatic and mammary tissue by hops (Humulus lupulus) in vitro and in vivo.
abstract: METHODS
  Hops contain the phytoestrogen, 8-prenylnaringenin, and the cytoprotective compound, xanthohumol (XH). XH induces the detoxification enzyme, NAD(P)H-quinone oxidoreductase (NQO1) in vitro; however, the tissue distribution of XH and 8-prenylnaringenin and their tissue-specific activity have not been analyzed.
  
  
  RESULTS
  An orally administered hop extract and subcutaneously injected XH were administered to Sprague-Dawley rats over 4 days. LC-MS-MS analysis of plasma, liver, and mammary gland revealed that XH accumulated in liver and mammary glands. Compared with the low level in the original extract, 8-prenylnaringenin was enriched in the tissues. Hops and XH-induced NQO1 in the liver, while only hops reduced NQO1 activity in the mammary gland. Mechanistic studies revealed that hops modulated NQO1 through three mechanisms. In liver cells, (i) XH modified Kelch-like ECH-associated protein leading to nuclear factor (erythroid-derived 2)-like 2 (Nrf2) translocation and antioxidant response element (ARE) activation; (ii) hop-mediated ARE induction was partially mediated through phosphorylation of Nrf2 by PKC; (iii) in breast cells, 8-prenylnaringenin reduced NQO1 likely through binding to estrogen receptorα, recruiting Nrf2, and downregulating ARE-regulated genes.
  
  
  CONCLUSIONS
  XH and 8-prenylnaringenin in dietary hops are bioavailable to the target tissues. While hops and XH might be cytoprotective in the liver, 8-prenylnaringenin seems responsible for hop-mediated NQO1 reduction in the mammary gland.
authors.affiliation: UIC/NIH Center for Botanical Dietary Supplements Research, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, IL 60612, USA. birgitd@uic.edu
authors.forename: Birgit M
authors.initials: BM
authors.lastname: Dietz
authors.forename: Ghenet K
authors.initials: GK
authors.lastname: Hagos
authors.forename: Jillian N
authors.initials: JN
authors.lastname: Eskra
authors.forename: Gihani T
authors.initials: GT
authors.lastname: Wijewickrama
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Anderson
authors.forename: Dejan
authors.initials: D
authors.lastname: Nikolic
authors.forename: Jian
authors.initials: J
authors.lastname: Guo
authors.forename: Brian
authors.initials: B
authors.lastname: Wright
authors.forename: Shao-Nong
authors.initials: SN
authors.lastname: Chen
authors.forename: Guido F
authors.initials: GF
authors.lastname: Pauli
authors.forename: Richard B
authors.initials: RB
authors.lastname: van Breemen
authors.forename: Judy L
authors.initials: JL
authors.lastname: Bolton
mesh_terms: D000818:Animals; D061745:Antioxidant Response Elements / Q000187:drug effects / Q000235:genetics; D005260:Female; D044950:Flavanones / Q000097:blood / Q000493:pharmacokinetics*; D005419:Flavonoids / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D027582:Humulus / Q000737:chemistry*; D008658:Inactivation, Metabolic; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D061986:MCF-7 Cells / Q000187:drug effects; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000201:enzymology*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010936:Plant Extracts / Q000493:pharmacokinetics / Q000494:pharmacology*; D011427:Propiophenones / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
chemical_list: C119737:8-prenylnaringenin; D044950:Flavanones; D005419:Flavonoids; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D010936:Plant Extracts; D011427:Propiophenones; D016660:NAD(P)H Dehydrogenase (Quinone); C507703:NQO1 protein, rat; D005982:Glutathione Transferase; D011493:Protein Kinase C; C104536:xanthohumol