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ToxSci Advance Access published online on June 30, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm168
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© 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 Boitier Eric*,1

* Department of Drug Safety Evaluation, sanofi aventis R&D, Centre de Recherche de Vitry/Alfortville-Evry, 13 quai Jules Guesde, 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. Tel.: 33.1.58.93.28.64. Fax: 33.1.58.93.81.97. E-mail: Eric.Boitier{at}sanofi-aventis.com; michel.cecile{at}gmail.com

Received April 5, 2007; revision received May 21, 2007; accepted May 22, 2007


  Abstract

Clofibric acid (CLO) is a non-genotoxic 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 non-necrogenic 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 non-tumoral 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 non-tumoral 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 non-genotoxic hepatocarcinogenic potential of drugs under development.

Key Words: Peroxisome proliferators; hepatocarcinogenesis; initiation; promotion; toxicogenomics; Clofibrate; Diethylnitrosamine.


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