title: 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 alpha GSTA1 and class pi 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.
authors.affiliation: Laboratory of Food and Biodynamics and the Division of Biomodeling, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan.
authors.forename: Yasujiro
authors.initials: Y
authors.lastname: Morimitsu
authors.forename: Yoko
authors.initials: Y
authors.lastname: Nakagawa
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Hayashi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Fujii
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kumagai
authors.forename: Yoshimasa
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Osawa
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Horio
authors.forename: Ken
authors.initials: K
authors.lastname: Itoh
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Iida
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Koji
authors.initials: K
authors.lastname: Uchida
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000493:pharmacokinetics*; D002273:Carcinogens / Q000493:pharmacokinetics*; D003001:Cloning, Molecular; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004790:Enzyme Induction; D005721:Glutamate-Cysteine Ligase / Q000378:metabolism; D005982:Glutathione Transferase / Q000096:biosynthesis / Q000378:metabolism*; D008658:Inactivation, Metabolic; D017879:Isothiocyanates; D007564:Japan; D007700:Kinetics; D016350:Leucine Zippers; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D051267:NF-E2-Related Factor 2; D010936:Plant Extracts / Q000737:chemistry; D018517:Plant Roots; D011994:Recombinant Proteins / Q000378:metabolism; D013454:Sulfoxides; D013861:Thiocyanates / Q000493:pharmacokinetics*; D015534:Trans-Activators / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D016588:Anticarcinogenic Agents; D002273:Carcinogens; D004268:DNA-Binding Proteins; D017879:Isothiocyanates; D051267:NF-E2-Related Factor 2; D010936:Plant Extracts; D011994:Recombinant Proteins; D013454:Sulfoxides; D013861:Thiocyanates; D015534:Trans-Activators; D016660:NAD(P)H Dehydrogenase (Quinone); D005982:Glutathione Transferase; D005721:Glutamate-Cysteine Ligase; C016766:sulforaphane