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Research Article

Induction of xenobiotic enzymes by the map kinase pathway and the antioxidant or electrophile response element (ARE/EpRE),†,

, , , , , & show all
Pages 255-271 | Published online: 04 Mar 2002
 

Abstract

Cellular responses to xenobiotic-induced stress can signal proliferation, differentiation, homeostasis, apoptosis, or necrosis. To better understand the underlying molecular mechanisms after exposure to xenobiotics or drugs, we studied the signal transduction pathways, the mitogen-activated protein kinase (MAPK), and the basic leucine zipper transcription factor Nrf2, activated by different agents in the induction of Phase II drug metabolizing enzymes (DMEs). The MAPKs, characterized as proline-directed serine/threonine kinases, are essential components of signaling pathways that convert various extracellular signals into intracellular responses through serial phosphorylation cascades. Once activated, MAPKs can phosphorylate many transcription factors, such as c-Jun, ATF-2, and ultimately lead to changes in gene expression. Two classes of Phase II gene inducers, which are also cancer chemopreventive agents, were studied: (1) the phenolic antioxidants, namely butylated hydroxyanisole (BHA) and its active de-methylated metabolite t-butylhydroquinone (tBHQ), and phenolic flavonoids such as green tea polyphenols (GTP) and (−)-epigallocatechin-3-gallate (EGCG); and (2) the naturally occurring isothiocyanates, namely phenethyl isothiocyanate (PEITC), and sulforaphane. BHA and tBHQ are both well-known phenolic antioxidants used as food preservatives, and strongly activate c-Jun N-terminal kinase 1 (JNK1), extracellular signal-regulated protein kinase 2 (ERK2), or p38, in a time- and dose-dependent fashion. Free radical scavengers N-acetyl-l-cysteine (NAC), or glutathione (GSH), inhibited ERK2 activation and, to a much lesser extent, JNK1 activation by BHA/tBHQ, implicating the role of oxidative stress. Under conditions where MAPKs were activated, BHA or GTP also activated ARE/EpRE (antioxidant/electrophile response element), with the induction of Phase II genes such as NQO. Transfection studies with various cDNAs encoding wild-type or dominant-negative mutants of MAPKs and/or transcription factor Nrf2, substantially modulated ARE-mediated luciferase reporter activity in the presence or absence of phenolic compounds. Other phytochemicals including PEITC, and sulforaphane, also differentially regulated the activities of MAPKs, Nrf2, and ARE-mediated luciferase reporter gene activity and Phase II enzyme induction. A model is proposed where these xenobiotics (BHA, tBHQ, GTP, EGCG, PEITC, sulforaphane) activate the MAPK pathway via an electrophilic-mediated stress response, leading to the transcription activation of Nrf2/Maf heterodimers on ARE/EpRE enhancers, with the subsequent induction of cellular defense/detoxifying genes including Phase II DMEs, which may protect the cells against toxic environmental insults and thereby enhance cell survival. The studies of these signaling pathways may yield insights into the fate of cells upon exposure to xenobiotics.

Abbreviations:
AP-1=

activated protein 1

ARE/EpRE=

antioxidant response element/electrophile response element

ASK1=

apoptosis signal-regulating kinase 1

BHA=

2(3)-tert-butyl-4-hydroxyanisole

CYP=

cytochrome P450

EGCG=

(−)-epigallocatechin-3-gallate

EPH=

epoxide hydrolases

ERK2=

extracellular signal-regulated protein kinase 2

GSH=

glutathione

GST=

glutathione S-transferases

GTP=

green tea polyphenols

HO=

heme oxygenase

JNK1=

c-jun N-terminal kinase 1

MAPK=

mitogen-activated protein kinase

MAPKKK=

MAP kinase kinase kinase

MEK=

MAPK/extracellular signal-regulated kinase kinase

MEKK1=

MAPK/extracellular signal-regulated kinase kinase kinase 1

MKK=

MAPK kinase

NAT=

N-acetyltransferase

NFκB=

nuclear factor κB

NQO=

DT-diaphorase or NAD(P)H:quinone oxidoreductase or NAD(P)H:menadione reductase

Nrf1=

Nrf2, nuclear factor-erythroid 2 (NF-E2) related factors 1, 2

PEITC=

phenethyl isothiocyanate

ROS=

reactive oxygen species

SAPK=

stress-activated protein kinase

ST=

sulfotransferases

TAK1=

transforming growth factor-β-activated kinase 1

tBHQ=

tert-butylhydroquinone

UGT=

UDP-glucuronosyltransferases

XRE/AhRE=

xenobiotics response element/aromatic hydrocarbon response element

Abbreviations:
AP-1=

activated protein 1

ARE/EpRE=

antioxidant response element/electrophile response element

ASK1=

apoptosis signal-regulating kinase 1

BHA=

2(3)-tert-butyl-4-hydroxyanisole

CYP=

cytochrome P450

EGCG=

(−)-epigallocatechin-3-gallate

EPH=

epoxide hydrolases

ERK2=

extracellular signal-regulated protein kinase 2

GSH=

glutathione

GST=

glutathione S-transferases

GTP=

green tea polyphenols

HO=

heme oxygenase

JNK1=

c-jun N-terminal kinase 1

MAPK=

mitogen-activated protein kinase

MAPKKK=

MAP kinase kinase kinase

MEK=

MAPK/extracellular signal-regulated kinase kinase

MEKK1=

MAPK/extracellular signal-regulated kinase kinase kinase 1

MKK=

MAPK kinase

NAT=

N-acetyltransferase

NFκB=

nuclear factor κB

NQO=

DT-diaphorase or NAD(P)H:quinone oxidoreductase or NAD(P)H:menadione reductase

Nrf1=

Nrf2, nuclear factor-erythroid 2 (NF-E2) related factors 1, 2

PEITC=

phenethyl isothiocyanate

ROS=

reactive oxygen species

SAPK=

stress-activated protein kinase

ST=

sulfotransferases

TAK1=

transforming growth factor-β-activated kinase 1

tBHQ=

tert-butylhydroquinone

UGT=

UDP-glucuronosyltransferases

XRE/AhRE=

xenobiotics response element/aromatic hydrocarbon response element

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