Induction of detoxifying enzymes by garlic organosulfur compounds through transcription factor Nrf2: Effect of chemical structure and stress signals

Chi Chen, Daniel Pung, Vasco Leong, Vidya Hebbar, Guoxiang Shen, Sujit Nair, Wenge Li, A. N. Tony Kong

Research output: Contribution to journalArticle

197 Citations (Scopus)

Abstract

Garlic organosulfur compounds (OSCs) are recognized as a group of potential chemopreventive compounds. It is known that garlic OSCs can modulate drug metabolism systems, especially various phase II detoxifying enzymes, though the mechanism underlying their inductive effect on these enzymes remains largely unknown. In the present study, we investigated the transcriptional levels of NAD(P)H:quinone oxidoreductase 1 (NQO1) and heme oxygenase 1 (HO1) genes, the reporter activity mediated by antioxidant response element (ARE), and the protein level of transcription factor nuclear factor E2-related factor 2 (Nrf2), after administration of three major garlic OSCs - diallyl sulfide (DAS), diallyl disulfide (DADS), and diallyl trisulfide (DATS) - in human hepatoma HepG2 cells. Our results showed that ARE activation and Nrf2 protein accumulation were well correlated with phase II gene expression induction. The structure-activity relationship study indicated that the third sulfur in the structure of OSCs contributed substantially to their bioactivities, and that allyl-containing OSCs were more potent than propyl-containing OSCs. To better understand the signaling events involved in the upregulation of detoxifying enzymes by DATS, ARE activity and Nrf2 protein levels were examined after transient transfection of HepG2 cells with mutant Nrf2, cotreatment with antioxidants, and pretreatment with protein kinase inhibitors. DATS-induced ARE activity was inhibited by dominant-negative Nrf2 Kelch-like ECH-associating protein 1 and constructs. Cotreatment with thiol antioxidants decreased the ARE activity and Nrf2 protein level induced by DATS. Three major mitogen-activated protein kinases (MAPKs) - extracellular signal-regulated protein kinase, c-Jun N-terminal kinase, and p38 - were activated by DATS treatment. However, the inhibition of these MAPKs did not affect DATS-induced ARE activity. Pretreatment with various upstream protein kinase inhibitors showed that the protein kinase C pathway was not directly involved in DATS-induced ARE activity, but instead the calcium-dependent signaling pathway appeared to play a role in the DATS-induced cytoprotective effect.

Original languageEnglish (US)
Pages (from-to)1578-1590
Number of pages13
JournalFree Radical Biology and Medicine
Volume37
Issue number10
DOIs
StatePublished - Nov 15 2004
Externally publishedYes

Fingerprint

NF-E2-Related Factor 2
Antioxidant Response Elements
Enzyme Induction
Garlic
Transcription Factors
Enzymes
Hep G2 Cells
Protein Kinase Inhibitors
Mitogen-Activated Protein Kinases
Proteins
Antioxidants
Heme Oxygenase-1
Calcium Signaling
diallyl trisulfide
JNK Mitogen-Activated Protein Kinases
Extracellular Signal-Regulated MAP Kinases
Structure-Activity Relationship
Bioactivity
Reporter Genes
Sulfur

Keywords

  • Antioxidant response element
  • Diallyl disulfide
  • Diallyl trisulfide
  • Garlic organosulfur compounds
  • Kelch-like ECH-associating protein 1
  • Mitogen-activated protein kinases
  • Nuclear factor E2-related factor
  • Thiol antioxidants

ASJC Scopus subject areas

  • Medicine(all)
  • Toxicology
  • Clinical Biochemistry

Cite this

Induction of detoxifying enzymes by garlic organosulfur compounds through transcription factor Nrf2 : Effect of chemical structure and stress signals. / Chen, Chi; Pung, Daniel; Leong, Vasco; Hebbar, Vidya; Shen, Guoxiang; Nair, Sujit; Li, Wenge; Tony Kong, A. N.

In: Free Radical Biology and Medicine, Vol. 37, No. 10, 15.11.2004, p. 1578-1590.

Research output: Contribution to journalArticle

Chen, Chi ; Pung, Daniel ; Leong, Vasco ; Hebbar, Vidya ; Shen, Guoxiang ; Nair, Sujit ; Li, Wenge ; Tony Kong, A. N. / Induction of detoxifying enzymes by garlic organosulfur compounds through transcription factor Nrf2 : Effect of chemical structure and stress signals. In: Free Radical Biology and Medicine. 2004 ; Vol. 37, No. 10. pp. 1578-1590.
@article{2cec29fce59a4ff9969346c7a2051640,
title = "Induction of detoxifying enzymes by garlic organosulfur compounds through transcription factor Nrf2: Effect of chemical structure and stress signals",
abstract = "Garlic organosulfur compounds (OSCs) are recognized as a group of potential chemopreventive compounds. It is known that garlic OSCs can modulate drug metabolism systems, especially various phase II detoxifying enzymes, though the mechanism underlying their inductive effect on these enzymes remains largely unknown. In the present study, we investigated the transcriptional levels of NAD(P)H:quinone oxidoreductase 1 (NQO1) and heme oxygenase 1 (HO1) genes, the reporter activity mediated by antioxidant response element (ARE), and the protein level of transcription factor nuclear factor E2-related factor 2 (Nrf2), after administration of three major garlic OSCs - diallyl sulfide (DAS), diallyl disulfide (DADS), and diallyl trisulfide (DATS) - in human hepatoma HepG2 cells. Our results showed that ARE activation and Nrf2 protein accumulation were well correlated with phase II gene expression induction. The structure-activity relationship study indicated that the third sulfur in the structure of OSCs contributed substantially to their bioactivities, and that allyl-containing OSCs were more potent than propyl-containing OSCs. To better understand the signaling events involved in the upregulation of detoxifying enzymes by DATS, ARE activity and Nrf2 protein levels were examined after transient transfection of HepG2 cells with mutant Nrf2, cotreatment with antioxidants, and pretreatment with protein kinase inhibitors. DATS-induced ARE activity was inhibited by dominant-negative Nrf2 Kelch-like ECH-associating protein 1 and constructs. Cotreatment with thiol antioxidants decreased the ARE activity and Nrf2 protein level induced by DATS. Three major mitogen-activated protein kinases (MAPKs) - extracellular signal-regulated protein kinase, c-Jun N-terminal kinase, and p38 - were activated by DATS treatment. However, the inhibition of these MAPKs did not affect DATS-induced ARE activity. Pretreatment with various upstream protein kinase inhibitors showed that the protein kinase C pathway was not directly involved in DATS-induced ARE activity, but instead the calcium-dependent signaling pathway appeared to play a role in the DATS-induced cytoprotective effect.",
keywords = "Antioxidant response element, Diallyl disulfide, Diallyl trisulfide, Garlic organosulfur compounds, Kelch-like ECH-associating protein 1, Mitogen-activated protein kinases, Nuclear factor E2-related factor, Thiol antioxidants",
author = "Chi Chen and Daniel Pung and Vasco Leong and Vidya Hebbar and Guoxiang Shen and Sujit Nair and Wenge Li and {Tony Kong}, {A. N.}",
year = "2004",
month = "11",
day = "15",
doi = "10.1016/j.freeradbiomed.2004.07.021",
language = "English (US)",
volume = "37",
pages = "1578--1590",
journal = "Free Radical Biology and Medicine",
issn = "0891-5849",
publisher = "Elsevier Inc.",
number = "10",

}

TY - JOUR

T1 - Induction of detoxifying enzymes by garlic organosulfur compounds through transcription factor Nrf2

T2 - Effect of chemical structure and stress signals

AU - Chen, Chi

AU - Pung, Daniel

AU - Leong, Vasco

AU - Hebbar, Vidya

AU - Shen, Guoxiang

AU - Nair, Sujit

AU - Li, Wenge

AU - Tony Kong, A. N.

PY - 2004/11/15

Y1 - 2004/11/15

N2 - Garlic organosulfur compounds (OSCs) are recognized as a group of potential chemopreventive compounds. It is known that garlic OSCs can modulate drug metabolism systems, especially various phase II detoxifying enzymes, though the mechanism underlying their inductive effect on these enzymes remains largely unknown. In the present study, we investigated the transcriptional levels of NAD(P)H:quinone oxidoreductase 1 (NQO1) and heme oxygenase 1 (HO1) genes, the reporter activity mediated by antioxidant response element (ARE), and the protein level of transcription factor nuclear factor E2-related factor 2 (Nrf2), after administration of three major garlic OSCs - diallyl sulfide (DAS), diallyl disulfide (DADS), and diallyl trisulfide (DATS) - in human hepatoma HepG2 cells. Our results showed that ARE activation and Nrf2 protein accumulation were well correlated with phase II gene expression induction. The structure-activity relationship study indicated that the third sulfur in the structure of OSCs contributed substantially to their bioactivities, and that allyl-containing OSCs were more potent than propyl-containing OSCs. To better understand the signaling events involved in the upregulation of detoxifying enzymes by DATS, ARE activity and Nrf2 protein levels were examined after transient transfection of HepG2 cells with mutant Nrf2, cotreatment with antioxidants, and pretreatment with protein kinase inhibitors. DATS-induced ARE activity was inhibited by dominant-negative Nrf2 Kelch-like ECH-associating protein 1 and constructs. Cotreatment with thiol antioxidants decreased the ARE activity and Nrf2 protein level induced by DATS. Three major mitogen-activated protein kinases (MAPKs) - extracellular signal-regulated protein kinase, c-Jun N-terminal kinase, and p38 - were activated by DATS treatment. However, the inhibition of these MAPKs did not affect DATS-induced ARE activity. Pretreatment with various upstream protein kinase inhibitors showed that the protein kinase C pathway was not directly involved in DATS-induced ARE activity, but instead the calcium-dependent signaling pathway appeared to play a role in the DATS-induced cytoprotective effect.

AB - Garlic organosulfur compounds (OSCs) are recognized as a group of potential chemopreventive compounds. It is known that garlic OSCs can modulate drug metabolism systems, especially various phase II detoxifying enzymes, though the mechanism underlying their inductive effect on these enzymes remains largely unknown. In the present study, we investigated the transcriptional levels of NAD(P)H:quinone oxidoreductase 1 (NQO1) and heme oxygenase 1 (HO1) genes, the reporter activity mediated by antioxidant response element (ARE), and the protein level of transcription factor nuclear factor E2-related factor 2 (Nrf2), after administration of three major garlic OSCs - diallyl sulfide (DAS), diallyl disulfide (DADS), and diallyl trisulfide (DATS) - in human hepatoma HepG2 cells. Our results showed that ARE activation and Nrf2 protein accumulation were well correlated with phase II gene expression induction. The structure-activity relationship study indicated that the third sulfur in the structure of OSCs contributed substantially to their bioactivities, and that allyl-containing OSCs were more potent than propyl-containing OSCs. To better understand the signaling events involved in the upregulation of detoxifying enzymes by DATS, ARE activity and Nrf2 protein levels were examined after transient transfection of HepG2 cells with mutant Nrf2, cotreatment with antioxidants, and pretreatment with protein kinase inhibitors. DATS-induced ARE activity was inhibited by dominant-negative Nrf2 Kelch-like ECH-associating protein 1 and constructs. Cotreatment with thiol antioxidants decreased the ARE activity and Nrf2 protein level induced by DATS. Three major mitogen-activated protein kinases (MAPKs) - extracellular signal-regulated protein kinase, c-Jun N-terminal kinase, and p38 - were activated by DATS treatment. However, the inhibition of these MAPKs did not affect DATS-induced ARE activity. Pretreatment with various upstream protein kinase inhibitors showed that the protein kinase C pathway was not directly involved in DATS-induced ARE activity, but instead the calcium-dependent signaling pathway appeared to play a role in the DATS-induced cytoprotective effect.

KW - Antioxidant response element

KW - Diallyl disulfide

KW - Diallyl trisulfide

KW - Garlic organosulfur compounds

KW - Kelch-like ECH-associating protein 1

KW - Mitogen-activated protein kinases

KW - Nuclear factor E2-related factor

KW - Thiol antioxidants

UR - http://www.scopus.com/inward/record.url?scp=5344220933&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=5344220933&partnerID=8YFLogxK

U2 - 10.1016/j.freeradbiomed.2004.07.021

DO - 10.1016/j.freeradbiomed.2004.07.021

M3 - Article

C2 - 15477009

AN - SCOPUS:5344220933

VL - 37

SP - 1578

EP - 1590

JO - Free Radical Biology and Medicine

JF - Free Radical Biology and Medicine

SN - 0891-5849

IS - 10

ER -