title: Structure activity relationship of carotenoid derivatives in activation of the electrophile/antioxidant response element transcription system.
abstract: Induction of phase II detoxifying enzymes is a major cellular strategy for reducing the risk of cancer. We previously reported that carotenoids activate the electrophile/antioxidant response element (EpRE/ARE) transcription system and induced the expression of phase II enzymes. Various electrophilic phytonutrients have been shown to induce the EpRE/ARE system by disrupting the inhibitory activity of Keap1 on Nrf2, the major EpRE/ARE activating transcription factor. However, hydrophobic carotenoids such as lycopene lack any electrophilic group and, thus, are unlikely to directly activate Nrf2 and the EpRE/ARE system. Here we demonstrate that carotenoid oxidation products are the active mediators in the stimulation of the EpRE/ARE system by carotenoids. Two lines of evidence support this conclusion. (A) The oxidized derivatives, extracted by ethanol from partially oxidized lycopene, transactivated EpRE/ARE with a potency similar to that of the unextracted lycopene mixture, whereas the intact carotenoid showed a nonsignificant effect. (B) Using a series of characterized mono- and diapocarotenoids that potentially can be derived from in vivo metabolism of carotenoids we defined the following structure-activity rules for activation of EpRE/ARE: (I) aldehydes and not acids are the active molecules; (II) the activity depends on the relative position of the methyl group to the terminal aldehyde which determines the reactivity of the conjugated double bond; (III) the optimal length of a dialdehyde derivative is 12 carbons in the main chain of the molecule. The apocarotenals inhibited breast and prostate cancer cell growth with a similar order of potency to the activation of EpRE/ARE. These results may provide a mechanistic explanation for the cancer preventive activity of carotenoids.
authors.affiliation: Clinical Biochemistry, Faculty of Health Sciences, Ben-Gurion University and Soroka Medical Center of Kupat Holim, Beer-Sheva, Israel.
authors.forename: Karin
authors.initials: K
authors.lastname: Linnewiel
authors.forename: Hansgeorg
authors.initials: H
authors.lastname: Ernst
authors.forename: Catherine
authors.initials: C
authors.lastname: Caris-Veyrat
authors.forename: Anat
authors.initials: A
authors.lastname: Ben-Dor
authors.forename: Arie
authors.initials: A
authors.lastname: Kampf
authors.forename: Hagar
authors.initials: H
authors.lastname: Salman
authors.forename: Michael
authors.initials: M
authors.lastname: Danilenko
authors.forename: Joseph
authors.initials: J
authors.lastname: Levy
authors.forename: Yoav
authors.initials: Y
authors.lastname: Sharoni
mesh_terms: D000447:Aldehydes / Q000737:chemistry / Q000494:pharmacology; D000975:Antioxidants / Q000378:metabolism*; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism; D002338:Carotenoids / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D008954:Models, Biological; D010084:Oxidation-Reduction; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism; D020218:Response Elements / Q000187:drug effects* / Q000502:physiology; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic / Q000187:drug effects* / Q000502:physiology; D015533:Transcriptional Activation / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: D000447:Aldehydes; D000975:Antioxidants; D002338:Carotenoids