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ToxSci Advance Access originally published online on July 17, 2007
Toxicological Sciences 2007 99(2):446-454; doi:10.1093/toxsci/kfm183
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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

Comparison of Mode of Action of Four Hepatocarcinogens: A Model-Based Approach

Jutta Groos*, Peter Bannasch{dagger}, Michael Schwarz{ddagger} and Annette Kopp-Schneider*,1

* Central Unit Biostatistics {dagger} Department of Cellular and Molecular Pathology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69009 Heidelberg, Germany {ddagger} Department of Toxicology, Institute of Pharmacology and Toxicology, University of Tuebingen, D-72074 Tuebingen, Germany

1 To whom correspondence should be addressed at German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69009 Heidelberg, Germany. Fax: +49-6221-42-2397. E-mail: kopp{at}dkfz.de.

Received March 20, 2007; accepted July 11, 2007


  Abstract

Within the scope of the Rat Liver Foci Bioassay the model carcinogens N-nitrosomorpholine (NNM), 2-acetylaminoflouren (2-AAF), phenobarbital (PB), and clofibrate (CF) were analyzed concerning their potency and dose–response relationship to induce foci of altered hepatocytes (FAHs), which are known to be precursor lesions of liver adenoma and carcinoma. The medium-term experiment follows an initiation–promotion protocol using diethylnitrosamine (DEN) as initiator. The present report deals with the application of two biologically based models for hepatocarcinogenesis, the two-stage clonal expansion model (TSCEM), and a color-shift model with beta distributed growth rates (CSMbeta). Both models yield similar conclusions concerning the mode of action of the carcinogens. However, the fit of CSMbeta appears closer to the observations than the fit of TSCEM. The analysis shows that application of a single dose of DEN has a persistent effect on the rate of FAH induction, especially in female rats. Overall, striking differences in the effect of the carcinogens were observed between male and female animals. 2-AAF shows a strong promoting effect in males, whereas in females the initiating effect dominates. NNM has both initiating and promoting effect, but in females, the rate of FAH formation seems to reach saturation at high dose. In the doses applied in the present experiment, PB has the weakest carcinogenic effect. Although PB alone does not induce FAH during the observation period, it increases the rate of FAH formation when applied following initiation with DEN. CF reduces the number and area fraction of GSTP-stained FAH, probably because it suppresses the placental form of glutathione S-transferase–positive phenotype.

Key Words: foci of altered hepatocytes; carcinogenesis model; initiation; promotion.


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