A Sulforaphane Analogue That Potently Activates the Nrf2-dependent Detoxification Pathway

Abstract

Exposure of cells to a wide variety of chemoprotective compounds confers resistance to a broad set of carcinogens. For a subset of the chemoprotective compounds, protection is generated by an increase in the abundance of the protective phase II detoxification enzymes, such as glutathione S-transferase (GST). We have recently developed a cell culture system, using rat liver epithelial RL 34 cells, that potently responds to the phenolic antioxidants resulting in the induction of GST activity (Kawamoto, Y., Nakamura, Y., Naito, Y., Torii, Y., Kumagai, T., Osawa, T., Ohigashi, H., Satoh, K., Imagawa, M., and Uchida, K. (2000) J. Biol. Chem. 275, 11291-11299.) In the present study, we investigated the phase II-inducing potency of an isothiocyanate compound in vitro and in vivo and examined a possible induction mechanism. Based on an extensive screening of vegetable extracts for GST inducer activity in RL34 cells, we found Japanese horseradish, wasabi (Wasabia japonica, syn. Eutrema wasabi), as the richest source and identified 6-methylsulfinylhexyl isothiocyanate (6-HITC), an analogue of sulforaphane (4-methylsulfinylbutyl isothiocyanate) isolated from broccoli, as the major GST inducer in wasabi. 6-HITC potently induced both class ␣ GSTA1 and class GSTP1 isozymes in RL34 cells. In animal experiments, we found that 6-MSHI was rapidly absorbed into the body and induced hepatic phase II detoxification enzymes more potently than sulforaphane. The observations that (i) 6-HITC activated the antioxidant response element (ARE), (ii) 6-HITC induced nuclear localization of the transcription factor Nrf2 that binds to ARE, and (iii) the induction of phase II enzyme genes by 6-HITC was completely abrogated in the nrf2-deficient mice, suggest that 6-HITC is a potential activator of the Nrf2/ARE-dependent detoxification pathway.

Sulforaphane homologues: Enantiodivergent synthesis of both enantiomers, activation of the Nrf2 transcription factor and selective cytotoxic activity

“…The presence of the sulfinyl group is not limited to SFN, but has been described for other isothiocyanates such as iberin (1-isothiocyanato-3-(methylsulfinyl)-propane) [25], 1-isothiocyanato-6-(methylsulfinyl)-hexane (6-HITC) [26], 1-isothiocyanato-7-(methylsulfinyl)-heptane (7-HITC), and 1-isothiocyanato-8-(methylsulfinyl)-octane (8-OITC) [27]. Among these homologues 6-HITC, found in Japanese horseradish, wasabi (Wasabia japonica, syn.…”

6-Methylsulfinylhexyl Isothiocyanate, an Antioxidant Derived from Wasabia japonica MATUM, Ameliorates Diabetic Nephropathy in Type 2 Diabetic Mice

“…6-MSITC isolated from wasabi induces GST in vitro (Morimitsu et al, 2002); thus, 6-MSITC may also act as an antioxidant in vivo. In the present study, we examined whether dietary WP and 6-MSITC could preserve renal function in type 2 diabetic mice.…”

“…Kinae et al (2000) reported the antioxidative activity of wasabi samples determined by Fenton reaction-1ipid peroxidation system in vitro. Morimitsu et al (2002) have reported that 6-MSITC activated the antioxidant response element (ARE), induced nuclear localization of the transcription factor NrF2 that binds to ARE, and induced phase 11 enzymes such as the glutathione S-transferase (GST). Thus, 6-MSITC may act as an antioxidant agent in vivo.…”

Anti-obesity Effects of Wasabi Leaf Extract on Rats Fed a High-fat Diet are Related to Upregulation of mRNA Expression of β3-adrenergic Receptors in Interscapular Brown Adipose Tissue

“…Grated wasabi rhizome, which contains various isothiocyanates, is a popular condiment in Japan. These isothiocyanates have many physiological functions, including anti-microbial (Isshiki et al, 1992), anti-platelet (Morimitsu et al, 2000), anti-cancer, antioxidative (Morimitsu et al, 2000(Morimitsu et al, , 2002, anti-inflammatory (Uto et al, 2005), anti-diabetic (Fukuchi et al, 2004;Yoshida et al, 2011), and anti-allergic (Nagai and Okunishi, 2009;Yamada-Kato et al, 2012) activities. Furthermore, isothiocyanates are known ligands of transient receptor potential ankyrin 1 (TRPA1) (Jordt et al, 2004;Terada et al, 2015;Uchida et al, 2012).…”