Abstract
Cruciferous vegetables are rich sources of glucosinolates which are the biogenic precursor molecules of isothiocyanates (ITCs). The relationship between the consumption of cruciferous vegetables and chemoprotection has been widely documented in epidemiological studies. Phenethyl isothiocyanate (PEITC) occurs as its glucosinolate precursor gluconasturtiin in the cruciferous vegetable watercress (Nasturtium officinale). PEITC has multiple biological effects, including activation of cytoprotective pathways, such as those mediated by the transcription factor nuclear factor erythroid 2 p45‐related factor 2 (NRF2) and the transcription factor heat shock factor 1 (HSF1), and can cause changes in the epigenome. However, at high concentrations, PEITC leads to accumulation of reactive oxygen species and cytoskeletal changes, resulting in cytotoxicity. Underlying these activities is the sulfhydryl reactivity of PEITC with cysteine residues in its protein targets. This chemical reactivity highlights the critical importance of the dose of PEITC for achieving on‐target selectivity, which should be carefully considered in the design of future clinical trials.
Highlights
Cruciferous vegetables are rich sources of glucosinolates which are the of species, and about 15 other plant families.[1]
This chemical reactivity highlights the critical importance of the dose of Phenethyl isothiocyanate (PEITC) for achieving on-target selectivity, which should be carefully considered in the design of future clinical trials
In close agreement with the data in MEF cells, we found that following treatment with the lowest (1 μm) concentration of PEITC, the stabilization of NRF2 was attenuated in the KEAP1C151S/C151S primary macrophage cells compared to their wild-type counterparts (Figure 4B)
Summary
Oxidation–reduction reactions play a central role in numerous biological processes. Living organisms are constantly exposed to ROS (e.g., superoxide anion, hydrogen peroxide, hydroxyl anion, and singlet oxygen) or reactive nitrogen species (RNS; e.g., nitroxyl anion, peroxyl nitrate, nitric oxide, and nitrosyl cation) produced by both endogenous and exogenous sources. Chronic oxidative stress has been implicated in cancer,[10] diabetes,[11] neurodegenerative,[12] respiratory,[13] cardiovascular,[13b,14] and inflammatory[15] diseases as well as aging.[16] In order to protect themselves from such insults, eukaryotic cells have developed several complex mechanisms to restore cellular redox homeostasis One such mechanism is by inducing the production of antioxidant and cytoprotective proteins. Lower concentrations of PEITC were used for the experiments with primary macrophage cells than the concentrations used for MEF cells due to the greater inducer sensitivity of primary cells compared to established cell lines Together, these data strongly suggest that C151 in KEAP1 is the primary sensor for PEITC, but at high concentrations of the ITC, this cysteine becomes “saturated,” and other cysteines are modified, leading to NRF2 stabilization. These results confirm that cysteine reactivity underlies the multiple biological activities of PEITC
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