Skip Navigation



ToxSci Advance Access published online on October 26, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfj031
This Article
Right arrow Advance Access manuscript (PDF) Freely available
Right arrow All Versions of this Article:
89/2/515    most recent
kfj031v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Lu, Y.
Right arrow Articles by Cederbaum, A. I.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lu, Y.
Right arrow Articles by Cederbaum, A. I.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received October 17, 2005
Accepted October 21, 2005

Systems Toxicology

Cisplatin-Induced Hepatotoxicity is Enhanced by Elevated Expression of Cytochrome P450 2E1

Yongke Lu 1 and Arthur I. Cederbaum 1*

1 The Department of Pharmacology and Biological Chemistry, Box 1603, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029

* To whom correspondence should be addressed.
Arthur I. Cederbaum, E-mail: Arthur.cederbaum{at}mssm.edu


  Abstract

In this study, the possible potentiation of ciplatin-induced hepatotoxicity by cytochrome P450 2E1 (CYP2E1) was examined both in vitro and in vivo. Transfected HepG2 cells expressing CYP2E1 (E47 cells) and not expressing CYP2E1 (C34 cells) were used as an in vitro model, and mice drinking 2% acetone for 7 days to induce CYP2E1 were used as an in vivo model. Exposure of E47 cells to cisplatin caused a much greater loss of cell viability, more striking depletion of GSH, and higher ROS production as compared with C34 cells. The prooxidant L-buthionine-[R,S]-sulfoximine (BSO) which depletes GSH enhanced cisplatin-induced loss of cell viability, whereas the antioxidant glutathione ethyl ester, or the iron chelator deferoxamine mesylate (DFO) protected against the cisplatin-induced loss of E47 cell viability. Diallyl sulfide (DAS), an inhibitor of CYP2E1, also protected against the cisplatin toxicity in the E47 cells. After being injected with cisplatin (ip, 45mg/kg), mice drinking 2% acetone with increased CYP2E1 levels exhibited more elevated levels of serum ALT and AST, liver caspase-3 activity and positive staining of TUNEL increased, histopathology indicated the presence of necrotic foci in livers of acetone plus cisplatin-treated mice; in the meanwhile, lipid peroxidation and protein oxidation as indicated by carbonyl formation, staining of 3-nitrotyrosine (3-NT) and iron were higher in cisplatin plus acetone group, compared with cisplatin alone group. Both in vitro and in vivo results indicate that elevated CYP2E1 enhances cisplatin-induced hepatotoxicity, and the mechanism maybe involves increased production of ROS and oxidative stress.

Keywords: cytochrome P450 2E1; acetone; cisplatin; hepatotoxicity; oxidative stress; HepG2 cell.
Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Pharmacol. Rev.Home page
N. Anderson and J. Borlak
Molecular Mechanisms and Therapeutic Targets in Steatosis and Steatohepatitis
Pharmacol. Rev., September 1, 2008; 60(3): 311 - 357.
[Abstract] [Full Text] [PDF]

Home page
 CarcinogenesisHome page
K. Johansson, K. Ahlen, R. Rinaldi, K. Sahlander, A. Siritantikorn, and R. Morgenstern
Microsomal glutathione transferase 1 in anticancer drug resistance
Carcinogenesis, February 1, 2007; 28(2): 465 - 470.
[Abstract] [Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.