CYP2E1 Overexpression Alters Hepatocyte Death from Menadione and Fatty Acids by Activation of ERK1/2 Signaling

Jörn M. Schattenberg, Yongjun Wang, Raina M. Rigoli, Dennis R. Koop, Mark J. Czaja

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

Chronic oxidative stress induced by overexpression of the cytochrome P450 isoform 2E1 (CYP2E1) has been implicated in hepatocyte injury and death. However, the mechanism by which CYP2E1 overexpression may promote cell death is unknown. Acute oxidative stress activates mitogen-activated protein kinases (MAPK), suggesting that chronic oxidant generation by CYP2E1 may regulate cellular responses through these signaling pathways. The effect of CYP2E1 overexpression on MAPK activation and their function in altering death responses of CYP2E1-overexpressing hepatocytes were investigated. Chronic CYP2E1 overexpression led to increased extracellular signal-regulated kinase 1/ 2 (ERK1/2) activation constitutively and in response to oxidant stress from the superoxide generator menadione. CYP2E1-overexpressing cells were resistant to menadione toxicity through an ERK1/2-dependent mechanism. Similar to menadione, the polyunsaturated fatty acid (PUFA) arachidonic acid (AA) induced an increased activation of ERK1/2 in hepatocytes that overexpressed CYP2E1. However, CYP2E1-overexpressing cells were sensitized to necrotic death from AA and the PUFA γ-linolenic acid, but not from saturated or monounsaturated fatty acids. Death from PUFA resulted from oxidative stress and was blocked by inhibition of ERK1/2, but not p38 MAPK or activator protein-1 signaling. CYP2E1 expression induced ERK1/2 activation through increased epidermal growth factor receptor (EGFR)/c-Raf signaling. Inhibition of EGFR signaling reversed CYP2E1-induced resistance to menadione and sensitization to AA toxicity. In conclusion, chronic CYP2E1 overexpression leads to sustained ERK1/2 activation mediated by EGFR/c-Raf signaling. This adaptive response in hepatocytes exposed to chronic oxidative stress confers differential effects on cellular survival, protecting against menadione-induced apoptosis, but sensitizing to necrotic death from PUFA.

Original languageEnglish (US)
Pages (from-to)444-455
Number of pages12
JournalHepatology
Volume39
Issue number2
DOIs
StatePublished - Feb 2004

Fingerprint

Vitamin K 3
Cytochrome P-450 CYP2E1
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Hepatocytes
Protein Isoforms
Fatty Acids
Unsaturated Fatty Acids
Oxidative Stress
Epidermal Growth Factor Receptor
Arachidonic Acid
Mitogen-Activated Protein Kinases
Oxidants
Monounsaturated Fatty Acids
alpha-Linolenic Acid
Transcription Factor AP-1
p38 Mitogen-Activated Protein Kinases
Superoxides
Cell Death

ASJC Scopus subject areas

  • Hepatology

Cite this

Schattenberg, J. M., Wang, Y., Rigoli, R. M., Koop, D. R., & Czaja, M. J. (2004). CYP2E1 Overexpression Alters Hepatocyte Death from Menadione and Fatty Acids by Activation of ERK1/2 Signaling. Hepatology, 39(2), 444-455. https://doi.org/10.1002/hep.20067

CYP2E1 Overexpression Alters Hepatocyte Death from Menadione and Fatty Acids by Activation of ERK1/2 Signaling. / Schattenberg, Jörn M.; Wang, Yongjun; Rigoli, Raina M.; Koop, Dennis R.; Czaja, Mark J.

In: Hepatology, Vol. 39, No. 2, 02.2004, p. 444-455.

Research output: Contribution to journalArticle

Schattenberg, Jörn M. ; Wang, Yongjun ; Rigoli, Raina M. ; Koop, Dennis R. ; Czaja, Mark J. / CYP2E1 Overexpression Alters Hepatocyte Death from Menadione and Fatty Acids by Activation of ERK1/2 Signaling. In: Hepatology. 2004 ; Vol. 39, No. 2. pp. 444-455.
@article{943739cd554d4663b5bc90d295d98c11,
title = "CYP2E1 Overexpression Alters Hepatocyte Death from Menadione and Fatty Acids by Activation of ERK1/2 Signaling",
abstract = "Chronic oxidative stress induced by overexpression of the cytochrome P450 isoform 2E1 (CYP2E1) has been implicated in hepatocyte injury and death. However, the mechanism by which CYP2E1 overexpression may promote cell death is unknown. Acute oxidative stress activates mitogen-activated protein kinases (MAPK), suggesting that chronic oxidant generation by CYP2E1 may regulate cellular responses through these signaling pathways. The effect of CYP2E1 overexpression on MAPK activation and their function in altering death responses of CYP2E1-overexpressing hepatocytes were investigated. Chronic CYP2E1 overexpression led to increased extracellular signal-regulated kinase 1/ 2 (ERK1/2) activation constitutively and in response to oxidant stress from the superoxide generator menadione. CYP2E1-overexpressing cells were resistant to menadione toxicity through an ERK1/2-dependent mechanism. Similar to menadione, the polyunsaturated fatty acid (PUFA) arachidonic acid (AA) induced an increased activation of ERK1/2 in hepatocytes that overexpressed CYP2E1. However, CYP2E1-overexpressing cells were sensitized to necrotic death from AA and the PUFA γ-linolenic acid, but not from saturated or monounsaturated fatty acids. Death from PUFA resulted from oxidative stress and was blocked by inhibition of ERK1/2, but not p38 MAPK or activator protein-1 signaling. CYP2E1 expression induced ERK1/2 activation through increased epidermal growth factor receptor (EGFR)/c-Raf signaling. Inhibition of EGFR signaling reversed CYP2E1-induced resistance to menadione and sensitization to AA toxicity. In conclusion, chronic CYP2E1 overexpression leads to sustained ERK1/2 activation mediated by EGFR/c-Raf signaling. This adaptive response in hepatocytes exposed to chronic oxidative stress confers differential effects on cellular survival, protecting against menadione-induced apoptosis, but sensitizing to necrotic death from PUFA.",
author = "Schattenberg, {J{\"o}rn M.} and Yongjun Wang and Rigoli, {Raina M.} and Koop, {Dennis R.} and Czaja, {Mark J.}",
year = "2004",
month = "2",
doi = "10.1002/hep.20067",
language = "English (US)",
volume = "39",
pages = "444--455",
journal = "Hepatology",
issn = "0270-9139",
publisher = "John Wiley and Sons Ltd",
number = "2",

}

TY - JOUR

T1 - CYP2E1 Overexpression Alters Hepatocyte Death from Menadione and Fatty Acids by Activation of ERK1/2 Signaling

AU - Schattenberg, Jörn M.

AU - Wang, Yongjun

AU - Rigoli, Raina M.

AU - Koop, Dennis R.

AU - Czaja, Mark J.

PY - 2004/2

Y1 - 2004/2

N2 - Chronic oxidative stress induced by overexpression of the cytochrome P450 isoform 2E1 (CYP2E1) has been implicated in hepatocyte injury and death. However, the mechanism by which CYP2E1 overexpression may promote cell death is unknown. Acute oxidative stress activates mitogen-activated protein kinases (MAPK), suggesting that chronic oxidant generation by CYP2E1 may regulate cellular responses through these signaling pathways. The effect of CYP2E1 overexpression on MAPK activation and their function in altering death responses of CYP2E1-overexpressing hepatocytes were investigated. Chronic CYP2E1 overexpression led to increased extracellular signal-regulated kinase 1/ 2 (ERK1/2) activation constitutively and in response to oxidant stress from the superoxide generator menadione. CYP2E1-overexpressing cells were resistant to menadione toxicity through an ERK1/2-dependent mechanism. Similar to menadione, the polyunsaturated fatty acid (PUFA) arachidonic acid (AA) induced an increased activation of ERK1/2 in hepatocytes that overexpressed CYP2E1. However, CYP2E1-overexpressing cells were sensitized to necrotic death from AA and the PUFA γ-linolenic acid, but not from saturated or monounsaturated fatty acids. Death from PUFA resulted from oxidative stress and was blocked by inhibition of ERK1/2, but not p38 MAPK or activator protein-1 signaling. CYP2E1 expression induced ERK1/2 activation through increased epidermal growth factor receptor (EGFR)/c-Raf signaling. Inhibition of EGFR signaling reversed CYP2E1-induced resistance to menadione and sensitization to AA toxicity. In conclusion, chronic CYP2E1 overexpression leads to sustained ERK1/2 activation mediated by EGFR/c-Raf signaling. This adaptive response in hepatocytes exposed to chronic oxidative stress confers differential effects on cellular survival, protecting against menadione-induced apoptosis, but sensitizing to necrotic death from PUFA.

AB - Chronic oxidative stress induced by overexpression of the cytochrome P450 isoform 2E1 (CYP2E1) has been implicated in hepatocyte injury and death. However, the mechanism by which CYP2E1 overexpression may promote cell death is unknown. Acute oxidative stress activates mitogen-activated protein kinases (MAPK), suggesting that chronic oxidant generation by CYP2E1 may regulate cellular responses through these signaling pathways. The effect of CYP2E1 overexpression on MAPK activation and their function in altering death responses of CYP2E1-overexpressing hepatocytes were investigated. Chronic CYP2E1 overexpression led to increased extracellular signal-regulated kinase 1/ 2 (ERK1/2) activation constitutively and in response to oxidant stress from the superoxide generator menadione. CYP2E1-overexpressing cells were resistant to menadione toxicity through an ERK1/2-dependent mechanism. Similar to menadione, the polyunsaturated fatty acid (PUFA) arachidonic acid (AA) induced an increased activation of ERK1/2 in hepatocytes that overexpressed CYP2E1. However, CYP2E1-overexpressing cells were sensitized to necrotic death from AA and the PUFA γ-linolenic acid, but not from saturated or monounsaturated fatty acids. Death from PUFA resulted from oxidative stress and was blocked by inhibition of ERK1/2, but not p38 MAPK or activator protein-1 signaling. CYP2E1 expression induced ERK1/2 activation through increased epidermal growth factor receptor (EGFR)/c-Raf signaling. Inhibition of EGFR signaling reversed CYP2E1-induced resistance to menadione and sensitization to AA toxicity. In conclusion, chronic CYP2E1 overexpression leads to sustained ERK1/2 activation mediated by EGFR/c-Raf signaling. This adaptive response in hepatocytes exposed to chronic oxidative stress confers differential effects on cellular survival, protecting against menadione-induced apoptosis, but sensitizing to necrotic death from PUFA.

UR - http://www.scopus.com/inward/record.url?scp=1242291933&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=1242291933&partnerID=8YFLogxK

U2 - 10.1002/hep.20067

DO - 10.1002/hep.20067

M3 - Article

VL - 39

SP - 444

EP - 455

JO - Hepatology

JF - Hepatology

SN - 0270-9139

IS - 2

ER -