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Volume 272, Number 46, Issue of November 14, 1997 pp. 28962-28970
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

Butylated Hydroxyanisole and Its Metabolite tert-Butylhydroquinone Differentially Regulate Mitogen-activated Protein Kinases
THE ROLE OF OXIDATIVE STRESS IN THE ACTIVATION OF MITOGEN-ACTIVATED PROTEIN KINASES BY PHENOLIC ANTIOXIDANTS

(Received for publication, June 17, 1997, and in revised form, August 22, 1997)

Rong Yu , Tse-Hua Tan ^§ and A.-N. Tony Kong

From the  Department of Pharmaceutics and Pharmacodynamics, Center for Pharmaceutical Biotechnology, College of Pharmacy, University of Illinois, Chicago, Illinois 60612 and the ^§ Department of Microbiology and Immunology, Baylor College of Medicine, Houston, Texas 77030

Phenolic antioxidant butylated hydroxyanisole (BHA) is a commonly used food preservative with broad biological activities, including protection against acute toxicity of chemicals, modulation of macromolecule synthesis and immune response, induction of phase II detoxifying enzymes, and especially its potential tumor-promoting activities. Understanding the molecular basis underlying these diverse biological actions of BHA is thus of great importance. Here we demonstrate that BHA is capable of activating distinct mitogen-activated protein kinases (MAPKs), extracellular signal-regulated protein kinase 2 (ERK2), and c-Jun N-terminal kinase 1 (JNK1). Activation of ERK2 by BHA was rapid and transient, whereas the JNK1 activation was relatively delayed and persistent. A major metabolite of BHA, tert-butylhydroquinone (tBHQ), also activated ERK2 but weakly stimulated JNK1 activity. Furthermore, tBHQ activation of ERK2 was late and prolonged, showing a kinetics different from that induced by BHA. ERK2 activation by both compounds required the involvement of an upstream signaling kinase MAPK/ERK kinase (MEK), as evidenced by the inhibitory effect of a MEK inhibitor, PD98059. Pretreatment with N-acetyl-L-cysteine, glutathione, or vitamin E attenuated ERK2 but not JNK1 activation by BHA and tBHQ. Modulation of intracellular H₂O₂ levels by direct addition of catalase or pretreatment with a catalase inhibitor, aminotriazole, also affected BHA- and tBHQ-stimulated ERK2 activity but not JNK1, indicating the involvement of oxidative stress in the ERK2 activation by these two compounds. However, we did not observe any generation of H₂O₂ after exposure of cells to BHA or tBHQ using a H₂O₂-sensitive fluorescent probe, 2,7-dichlorofluorescein diacetate. Instead, BHA and tBHQ substantially reduced the amount of intracellular H₂O₂. Furthermore, BHA and tBHQ activation of ERK2 was strongly inhibited by ascorbic acid and a peroxidase inhibitor, sodium azide, suggesting the potential role of phenoxyl radicals and/or their derivatives. Taken together, our results indicate that (i) BHA and its metabolite tBHQ differentially regulate MAPK pathways, and (ii) oxidative stress due to the generation of reactive intermediates, possibly phenoxyl radicals but not H₂O₂, is responsible for the ERK2 activation by BHA and tBHQ, whereas the JNK1 activation may require a distinct yet unknown mechanism.

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