Skip Navigation


ToxSci Advance Access originally published online on June 30, 2007
Toxicological Sciences 2007 99(1):58-69; doi:10.1093/toxsci/kfm168
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Supplementary Data
Right arrow All Versions of this Article:
99/1/58    most recent
kfm168v1
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 ISI Web of Science
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 Michel, C.
Right arrow Articles by Boitier, E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Michel, C.
Right arrow Articles by Boitier, E.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Diethylnitrosamine Initiation Does Not Alter Clofibric Acid–Induced Hepatocarcinogenesis in the Rat

Cecile Michel*, Chantal Desdouets{dagger}, Mohamed Slaoui*, Kevin Robert Isaacs{ddagger}, Ruth Angela Roberts§ and Eric Boitier*,1

* Department of Drug Safety Evaluation, sanofi aventis R&D, Centre de Recherche de Vitry/Alfortville-Evry, 94403 Vitry sur Seine, France {dagger} INSERM, U567, Paris, France {ddagger} 14 Rossett Park Road, Harrogate, North Yorkshire HG2 9NP, United Kingdom § AstraZeneca, Safety Assessment, Macclesfield, SK10 4TG Cheshire, United Kingdom

1 To whom correspondence should be addressed at sanofi aventis R&D, Centre de Recherche de Vitry/Alfortville-Evry, Drug Safety Evaluation, 13 quai Jules Guesde, 94403 Vitry sur Seine, France. Fax: +33-1-58-93-81-97. E-mail: Eric.Boitier{at}sanofi-aventis.com.

Received April 5, 2007; accepted May 22, 2007


  Abstract

Clofibric acid (CLO) is a nongenotoxic hepatocarcinogen in rodents that causes altered hepatocellular foci and/or neoplasms. Initiation by DNA-damaging agents such as diethylnitrosamine (DEN) accelerates focus and tumor appearance and could therefore significantly contribute to shortening of the regulatory 2-year rodent carcinogenicity bioassays. However, it is crucial to evaluate the histological and molecular impact of initiation with DEN on hepatocarcinogenesis promoted by CLO. Male F344 rats were given a single nonnecrogenic injection of DEN (0 or 30 mg/kg) followed by Control diet or CLO (5000 ppm) in diet for up to 20 months. Histopathology and gene expression profiling were performed in liver tumors and surrounding nontumoral liver tissues. The molecular signature of DEN was characterized and its histopathological and immunohistopathological effects on focus and tumor types were also determined. Although foci and tumors appeared earlier in the DEN + CLO–treated group compared to the group treated with CLO alone, DEN had little impact on gene expression in nontumoral tissues since the gene expression profiles were highly similar between Control and DEN-treated rats, and DEN + CLO- and CLO-treated rats. Finally, tumors obtained from DEN + CLO and CLO-treated groups displayed highly correlated gene expression profiles (r > 0.83, independently of the time-point). The pathways involved in tumor development revealed by Gene Ontology functional analysis are similar when driven either by spontaneous initiation or by a chemically induced initiation step. Our work described here may contribute to the design optimization of shorter preclinical tests for the evaluation of the nongenotoxic hepatocarcinogenic potential of drugs under development.

Key Words: peroxisome proliferators; hepatocarcinogenesis; initiation; promotion; toxicogenomics; Clofibrate; diethylnitrosamine.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?




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.