Regulation of cytochrome P450 2e1 expression by ethanol

Role of oxidative stress-mediated pkc/jnk/sp1 pathway

M. Jin, A. Ande, A. Kumar, Santosh Kumar

Research output: Contribution to journalArticle

75 Citations (Scopus)

Abstract

CYP2E1 metabolizes ethanol leading to production of reactive oxygen species (ROS) and acetaldehyde, which are known to cause not only liver damage but also toxicity to other organs. However, the signaling pathways involved in CYP2E1 regulation by ethanol are not clear, especially in extra-hepatic cells. This study was designed to examine the role of CYP2E1 in ethanolmediated oxidative stress and cytotoxicity, as well as signaling pathways by which ethanol regulates CYP2E1 in extra-hepatic cells. In this study, we used astrocytic and monocytic cell lines, because they are important cells in central nervous system . Our results showed that 100mM ethanol significantly induced oxidative stress, apoptosis, and cell death at 24 h in the SVGA astrocytic cell line, which was rescued by a CYP2E1 selective inhibitor, diallyl sulfide (DAS), CYP2E1 siRNA, and antioxidants (vitamins C and E). Further, we showed that DAS and vitamin C abrogated ethanol-mediated (50mM) induction of CYP2E1 at 6 h, as well as production of ROS at 2 h, suggesting the role of oxidative stress in ethanol-mediated induction of CYP2E1. We then investigated the role of the protein kinase C/c-Jun N-terminal kinase/specificity protein1 (PKC/JNK/SP1) pathway in oxidative stress-mediated CYP2E1 induction. Our results showed that staurosporine, a non-specific inhibitor of PKC, as well as specific PKCf inhibitor and PKCf siRNA, abolished ethanol-induced CYP2E1 expression. In addition, inhibitors of JNK (SP600125) and SP1 (mithramycin A) completely abrogated induction of CYP2E1 by ethanol in SVGA astrocytes. Subsequently, we showed that CYP2E1 is also responsible for ethanol-mediated oxidative stress and apoptotic cell death in U937 monocytic cell lines. Finally, our results showed that PKC/JNK/SP1 pathway is also involved in regulation of CYP2E1 in U937 cells. This study has clinical implications with respect to alcohol-associated neuroinflammatory toxicity among alcohol users.

Original languageEnglish (US)
JournalCell Death and Disease
Volume4
Issue number3
DOIs
StatePublished - Mar 1 2013

Fingerprint

Cytochrome P-450 CYP2E1
Oxidative Stress
Ethanol
U937 Cells
JNK Mitogen-Activated Protein Kinases
Cell Line
Protein Kinase C
Small Interfering RNA
Ascorbic Acid
Hepatocytes
Reactive Oxygen Species
Cell Death
Alcohols
Staurosporine
Acetaldehyde
Vitamin E
Astrocytes
Central Nervous System
Antioxidants

All Science Journal Classification (ASJC) codes

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

Cite this

Regulation of cytochrome P450 2e1 expression by ethanol : Role of oxidative stress-mediated pkc/jnk/sp1 pathway. / Jin, M.; Ande, A.; Kumar, A.; Kumar, Santosh.

In: Cell Death and Disease, Vol. 4, No. 3, 01.03.2013.

Research output: Contribution to journalArticle

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