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Citation
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HERO ID
2747837
Reference Type
Journal Article
Title
Structure activity relationship of carotenoid derivatives in activation of the electrophile/antioxidant response element transcription system
Author(s)
Linnewiel, K; Ernst, H; Caris-Veyrat, C; Ben-Dor, A; Kampf, A; Salman, H; Danilenko, M; Levy, J; Sharoni, Y
Year
2009
Is Peer Reviewed?
Yes
Journal
Free Radical Biology and Medicine
ISSN:
0891-5849
EISSN:
1873-4596
Volume
47
Issue
5
Page Numbers
659-667
Language
English
PMID
19524036
DOI
10.1016/j.freeradbiomed.2009.06.008
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.
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