QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.104.076737v1 312/3/998    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Jimenez-Lopez, J. M. Articles by Cederbaum, A. I. Search for Related Content PubMed PubMed Citation Articles by Jimenez-Lopez, J. M. Articles by Cederbaum, A. I. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB 12-O-TETRADECANOYLPHORBOL-13-ACETATE IRON

TOXICOLOGY

Protein Kinase C Signaling as a Survival Pathway against CYP2E1-Derived Oxidative Stress and Toxicity in HepG2 Cells

Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, New York, New York

Hepatic induction of CYP2E1 is a major pathway involved in oxidative stress and damage caused by chronic ethanol consumption; CYP2E1 also promotes the activation of a variety of hepatotoxins to reactive intermediates. Phorbol esters activate protein kinase C (PKC), thereby blocking cell differentiation and promoting tumor growth. In this study, we examined the possible role of PKC signaling as a survival pathway against CYP2E1-mediated toxicity using transfected HepG2 hepatoma cells stably overexpressing CYP2E1 (E47 cells). Cells were exposed to arachidonic acid (AA) plus Fe, which has been previously reported to cause a synergistic toxicity in E47 cells by a mechanism dependent on CYP2E1 activity and involving oxidative stress and lipid peroxidation. Phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA), but not the inactive analog 4--TPA, prevented lipid peroxidation, glutathione depletion, and loss of viability produced by AA + Fe in E47 cells. TPA also protected against the toxicity caused by AA alone, or by iron alone, in the E47 cells. TPA did not lower but instead induced catalytically active CYP2E1 in these cells. The protective effect of TPA on CYP2E1-dependent AA + Fe toxicity seemed to involve a PKC-related survival mechanism, since PKC inhibitors such as Ro 31-8425 (bisindolylmaleimide X hydrochloride) or staurosporine abolished that protection, and activation of PKC by TPA was an early event that occurs prior to the developing toxicity. In conclusion, PKC activation by TPA prevents CYP2E1-derived acute oxidative stress and toxicity in HepG2 cells, and this appears to involve maintenance of the intracellular redox homeostasis via PKC signal transduction.

Address correspondence to: Dr. Arthur I. Cederbaum, Department of Pharmacology and Biological Chemistry, Box 1603, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029. E-mail: arthur.cederbaum{at}mssm.edu

This article has been cited by other articles:

				B. Saberi, M. Shinohara, M. D. Ybanez, N. Hanawa, W. A. Gaarde, N. Kaplowitz, and D. Han Regulation of H2O2-induced necrosis by PKC and AMP-activated kinase signaling in primary cultured hepatocytes Am J Physiol Cell Physiol, July 1, 2008; 295(1): C50 - C63. [Abstract] [Full Text] [PDF]

				N. J. Hodges, R. M. Green, J. K. Chipman, and M. Graham Induction of DNA strand breaks and oxidative stress in HeLa cells by ethanol is dependent on CYP2E1 expression Mutagenesis, May 1, 2007; 22(3): 189 - 194. [Abstract] [Full Text] [PDF]

				J. Haorah, B. Knipe, J. Leibhart, A. Ghorpade, and Y. Persidsky Alcohol-induced oxidative stress in brain endothelial cells causes blood-brain barrier dysfunction J. Leukoc. Biol., December 1, 2005; 78(6): 1223 - 1232. [Abstract] [Full Text] [PDF]