A sulforaphane analogue that potently activates the Nrf2-dependent detoxification pathway

Yasujiro Morimitsu, Yoko Nakagawa, Kazuhiro Hayashi, Hiroyuki Fujii, Takeshi Kumagai, Yoshimasa Nakamura, Toshihiko Osawa, Fumihiko Horio, Ken Itoh, Katsuyuki Iida, Masayuki Yamamoto, Koji Uchida

Research output: Contribution to journalArticle

201 Citations (Scopus)

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-methylsulfinyl-butyl isothiocyanate) isolated from broccoli, as the major GST inducer in wasabi. 6-HITC potently induced both class α GSTA1 and class π 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.

Original languageEnglish
Pages (from-to)3456-3463
Number of pages8
JournalJournal of Biological Chemistry
Volume277
Issue number5
DOIs
Publication statusPublished - Feb 1 2002
Externally publishedYes

Fingerprint

Detoxification
Antioxidant Response Elements
Glutathione Transferase
Wasabia
Phase II Metabolic Detoxication
Enzymes
Liver
Brassica
Vegetables
Cell culture
Carcinogens
Isoenzymes
6-methylsulfinylhexyl isothiocyanate
sulforafan
Rats
Screening
Animals
Transcription Factors
Cell Culture Techniques
Antioxidants

ASJC Scopus subject areas

  • Biochemistry

Cite this

A sulforaphane analogue that potently activates the Nrf2-dependent detoxification pathway. / Morimitsu, Yasujiro; Nakagawa, Yoko; Hayashi, Kazuhiro; Fujii, Hiroyuki; Kumagai, Takeshi; Nakamura, Yoshimasa; Osawa, Toshihiko; Horio, Fumihiko; Itoh, Ken; Iida, Katsuyuki; Yamamoto, Masayuki; Uchida, Koji.

In: Journal of Biological Chemistry, Vol. 277, No. 5, 01.02.2002, p. 3456-3463.

Research output: Contribution to journalArticle

Morimitsu, Y, Nakagawa, Y, Hayashi, K, Fujii, H, Kumagai, T, Nakamura, Y, Osawa, T, Horio, F, Itoh, K, Iida, K, Yamamoto, M & Uchida, K 2002, 'A sulforaphane analogue that potently activates the Nrf2-dependent detoxification pathway', Journal of Biological Chemistry, vol. 277, no. 5, pp. 3456-3463. https://doi.org/10.1074/jbc.M110244200
Morimitsu, Yasujiro ; Nakagawa, Yoko ; Hayashi, Kazuhiro ; Fujii, Hiroyuki ; Kumagai, Takeshi ; Nakamura, Yoshimasa ; Osawa, Toshihiko ; Horio, Fumihiko ; Itoh, Ken ; Iida, Katsuyuki ; Yamamoto, Masayuki ; Uchida, Koji. / A sulforaphane analogue that potently activates the Nrf2-dependent detoxification pathway. In: Journal of Biological Chemistry. 2002 ; Vol. 277, No. 5. pp. 3456-3463.
@article{80a1165e056644fc859dfdca311a1e5e,
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-methylsulfinyl-butyl isothiocyanate) isolated from broccoli, as the major GST inducer in wasabi. 6-HITC potently induced both class α GSTA1 and class π 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.",
author = "Yasujiro Morimitsu and Yoko Nakagawa and Kazuhiro Hayashi and Hiroyuki Fujii and Takeshi Kumagai and Yoshimasa Nakamura and Toshihiko Osawa and Fumihiko Horio and Ken Itoh and Katsuyuki Iida and Masayuki Yamamoto and Koji Uchida",
year = "2002",
month = "2",
day = "1",
doi = "10.1074/jbc.M110244200",
language = "English",
volume = "277",
pages = "3456--3463",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "5",

}

TY - JOUR

T1 - A sulforaphane analogue that potently activates the Nrf2-dependent detoxification pathway

AU - Morimitsu, Yasujiro

AU - Nakagawa, Yoko

AU - Hayashi, Kazuhiro

AU - Fujii, Hiroyuki

AU - Kumagai, Takeshi

AU - Nakamura, Yoshimasa

AU - Osawa, Toshihiko

AU - Horio, Fumihiko

AU - Itoh, Ken

AU - Iida, Katsuyuki

AU - Yamamoto, Masayuki

AU - Uchida, Koji

PY - 2002/2/1

Y1 - 2002/2/1

N2 - 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-methylsulfinyl-butyl isothiocyanate) isolated from broccoli, as the major GST inducer in wasabi. 6-HITC potently induced both class α GSTA1 and class π 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.

AB - 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-methylsulfinyl-butyl isothiocyanate) isolated from broccoli, as the major GST inducer in wasabi. 6-HITC potently induced both class α GSTA1 and class π 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.

UR - http://www.scopus.com/inward/record.url?scp=0036479330&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0036479330&partnerID=8YFLogxK

U2 - 10.1074/jbc.M110244200

DO - 10.1074/jbc.M110244200

M3 - Article

C2 - 11706044

AN - SCOPUS:0036479330

VL - 277

SP - 3456

EP - 3463

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 5

ER -