Bi-Functional Induction of the Quinone Reductase and Cytochrome P450 1A1 by Youngiasides via Nrf2-ARE and AhR-XRE Pathways

Abstract

Cancer chemoprevention is defined as the use of phytochemicals (naturally occurring compounds or their synthetic derivatives) from dietary foods or natural products to inhibit, delay or reverse carcinogenesis or prevent the development of cancer.1,2) The important strategy of cancer chemoprevention aims to reduce the risk of cancer through modulation of detoxification enzymes involved in metabolic activation. The detoxification/excretion of carcinogens is one of the representative mechanisms of action of chemopreventive agents. 3)Dietary phytochemicals can be classified into two groups, termed mono-and bi-functional inducers. Mono-functional inducers upregulate a number of phase II detoxification enzymes, including quinone reductase (QR, also known as NAD(P)H: quinone oxidoreductase, NQO1) and glutathione S-transferases (GSTs). The bi-functional inducers upregulate a similar array of phase II enzymes as well as a number of phase I enzymes including cytochrome P450 1A1 (CYP1A1). 4) Since phase I enzymes are involved in both bioactivation and detoxification of carcinogens, the monofunctional inducers, which upregulate only phase II enzymes, are thought to be more closely associated with chemoprevention than are bi-functional inducers that upregulate both phase I and II enzymes. However, the bi-functional inducers can in some cases exert synergistic effects in cancer chemoprevention. Oltpraz, a plant-derived compound, is a promising bi-functional inducer and is found to increase levels of not only phase II, but also phase I, enzymes. 5)These inducers are known to regulate genes that encode detoxification enzymes and which involve two important promoter sites. One site is known as the antioxidant response element (ARE) associated with induction of phase II detoxification enzymes (mono-functional induction), 6,7) while the second is the xenobiotic response element (XRE) located in the promoters of genes encoding phase II, and some phase I, cytochrome P450 enzymes (bi-functional induction). 8) AREand XRE-containing promoters can be activated by binding of specific transcription factors such as nuclear factor E2 (NF-E2) p45-Nrf2 and AhR, respectively. Nrf2 is a member of the CNC (cap'n'collar) basic leucine zipper (bZIP) transcription factor family and AhR is a member of the basic helix-loop-helix/Per-Arnt-Sim (bHLH/PAS) family. 9) Nrf2 is known to translocate into the nucleus and recruit Maf proteins, which is followed by the activation of transcription of ARE-dependent genes.10) The ligand-bound AhR translocates into the nucleus where it binds as a heterodimer with the AhR nuclear translocator (Arnt) and activates the transcription of XRE-dependent genes.11) In addition, it was recently revealed that Nrf2 is one of the AhR target genes. 12,13) In Korea, early sprouts have been used of the compositae plant Crepidiastrum denticulatum (HOUTT.) PAK & KAWANO; however, induction of QR by this plant has not yet been reported. Further, the chemical structures of youngiaside A, B, and C isolated from C. denticulatum have been...

Crepidiastrum denticulatumExtract Protects the Liver Against Chronic Alcohol-Induced Damage and Fat Accumulation in Rats

“…[13][14][15] We recently reported that youngiasides A, B, and C isolated from CD could induce detoxification enzymes, quinone reductase and CYP 1A1, through the activation of Nrf2 and the aryl hydrocarbon receptor (AhR). 16 We also recently reported that CD had a protective effect in HepG2 cells against tert-butyl hydroperoxide, a strong inducer of oxidative stress, by increasing the glutathione level. 12 In the present study, we investigated whether CD extract may protect the liver against alcohol in vivo and whether there is potential for the development of a dietary supplement to improve liver function against chronic alcohol consumption.…”

Youngiasides A and C Isolated from Youngia denticulatum Inhibit UVB-Induced MMP Expression and Promote Type I Procollagen Production via Repression of MAPK/AP-1/NF-κB and Activation of AMPK/Nrf2 in HaCaT Cells and Human Dermal Fibroblasts

“…Isolation of chemical constituents ( Figure 1A) from Y. denticulatum was performed as previously described. 19 Cell Culture and UVB Irradiation. HaCaT and HDF cells were purchased from the American Type Culture Collection (Manassas, VA, USA).…”

Chikusetsusaponin IVa methyl ester induces cell cycle arrest by the inhibition of nuclear translocation of β-catenin in HCT116 cells

“…The cellular distribution of b-catenin was evaluated by an immunofluorescence assay using confocal microscopy (Leica, Wetzlar, Germany) as previously described [21]. In brief, HCT116 (7 Â 10 3 cells/well) cells were seeded onto glass cover slips in 24-well plates and were incubated for 24 h prior to treatment.…”