title: Identification of 3-hydroxy-beta-damascone and related carotenoid-derived aroma compounds as novel potent inducers of Nrf2-mediated phase 2 response with concomitant anti-inflammatory activity.
abstract: Structural comparison of apple constituents with known inducers of phase two cytoprotective enzymes led to the identification of 3-hydroxy-beta-damascone and related carotenoid derived aroma compounds as potent inducers of NAD(P)H:quinone reductase (QR) activity. Damascone-related compounds were found to be more potent inducers than ionone derivatives, with CD values (concentrations required to double the specific activity of QR in Hepa1c1c7 cell culture) in the range of 1.0-5.7 microM. QR induction by 3-hydroxy-beta-damascone was shown to be mediated via transcription factor Nrf2 signaling in transient transfection experiments. We further identified aroma compounds as potent inhibitors of LPS-induced inducible nitric oxide synthase activity in Raw 264.7 cell culture. Again, damascone derivatives were most potent with half-maximal inhibitory concentration values of 1.8-7.9 microM. These results reveal previously unrecognized cancer chemopreventive potential of aroma compounds such as beta-damascenone, 3-hydroxy-beta-damascone, and related substances, which may contribute to the cancer protective efficacy of apple products and other dietary sources in animal models.
authors.affiliation: Division of Toxicology and Cancer Risk Factors, German Cancer Research Center, Heidelberg, Germany. c.gerhauser@dkfz.de
authors.forename: Clarissa
authors.initials: C
authors.lastname: Gerhäuser
authors.forename: Karin
authors.initials: K
authors.lastname: Klimo
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hümmer
authors.forename: Jana
authors.initials: J
authors.lastname: Hölzer
authors.forename: Astrid
authors.initials: A
authors.lastname: Petermann
authors.forename: Antonio
authors.initials: A
authors.lastname: Garreta-Rufas
authors.forename: Frank-D
authors.initials: FD
authors.lastname: Böhmer
authors.forename: Peter
authors.initials: P
authors.lastname: Schreier
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival; D005638:Fruit / Q000737:chemistry; D006801:Humans; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D027845:Malus / Q000737:chemistry; D050217:Metabolic Detoxication, Phase II; D051379:Mice; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D045792:Norisoprenoids / Q000494:pharmacology*; D055549:Volatile Organic Compounds / Q000494:pharmacology
chemical_list: C476262:3-hydroxy-beta-damascone; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016588:Anticarcinogenic Agents; D008070:Lipopolysaccharides; D051267:NF-E2-Related Factor 2; D045792:Norisoprenoids; D055549:Volatile Organic Compounds; D052247:Nitric Oxide Synthase Type II; D016660:NAD(P)H Dehydrogenase (Quinone); C491732:Nqo1 protein, mouse