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

A. N.Tony Kong, Edward Owuor, Rong Yu, Vidya Hebbar, Chi Chen, Rong Hu, Sandhya Mandlekar

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285 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)255-271
Number of pages17
JournalDrug Metabolism Reviews
Issue number3-4
StatePublished - 2001

Bibliographical note

Funding Information:
*Presented at the 10th North American ISSX Meeting, Indianapolis, Indiana, October 24–28, 2000. †Supported in part by the National Institutes of Health grant R01-CA73674 to A.-N. T. Kong. ‡This paper was referred by Dr. F. P. Guengerich, Vanderbilt University, Nashville, TN 37232. §Corresponding author. Present address: Department of Pharmaceutics, College of Pharmacy, Rutgers University, and the Environmental and Occupational Health Sciences Institute, 160 Frelinghuysen Road, Room 228, Piscataway, NJ 08854. Fax: (732) 445-3831; E-mail: {Present address: Department of Drug Metabolism and Pharmacokinetics, DuPont Pharmaceutical Company, Newark, Delaware.


  • Chemopreventive agents
  • MAPK
  • Nrf2
  • Phase II drug metabolizing enzymes
  • Signal transduction


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