Prediction model of potential hepatocarcinogenicity of rat hepatocarcinogens using a large-scale toxicogenomics database
- Drug Developmental Research Laboratories, Shionogi and Co., Ltd., 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825 (Japan)
- Toxicogenomics Informatics Project, National Institute of Biomedical Innovation, 7-6-8 Asagi, Ibaraki, Osaka 567-0085 (Japan)
- Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Harumi-cho, Fuchu, Tokyo 183-8509 (Japan)
- National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501 (Japan)
The present study was performed to develop a robust gene-based prediction model for early assessment of potential hepatocarcinogenicity of chemicals in rats by using our toxicogenomics database, TG-GATEs (Genomics-Assisted Toxicity Evaluation System developed by the Toxicogenomics Project in Japan). The positive training set consisted of high- or middle-dose groups that received 6 different non-genotoxic hepatocarcinogens during a 28-day period. The negative training set consisted of high- or middle-dose groups of 54 non-carcinogens. Support vector machine combined with wrapper-type gene selection algorithms was used for modeling. Consequently, our best classifier yielded prediction accuracies for hepatocarcinogenicity of 99% sensitivity and 97% specificity in the training data set, and false positive prediction was almost completely eliminated. Pathway analysis of feature genes revealed that the mitogen-activated protein kinase p38- and phosphatidylinositol-3-kinase-centered interactome and the v-myc myelocytomatosis viral oncogene homolog-centered interactome were the 2 most significant networks. The usefulness and robustness of our predictor were further confirmed in an independent validation data set obtained from the public database. Interestingly, similar positive predictions were obtained in several genotoxic hepatocarcinogens as well as non-genotoxic hepatocarcinogens. These results indicate that the expression profiles of our newly selected candidate biomarker genes might be common characteristics in the early stage of carcinogenesis for both genotoxic and non-genotoxic carcinogens in the rat liver. Our toxicogenomic model might be useful for the prospective screening of hepatocarcinogenicity of compounds and prioritization of compounds for carcinogenicity testing. - Highlights: >We developed a toxicogenomic model to predict hepatocarcinogenicity of chemicals. >The optimized model consisting of 9 probes had 99% sensitivity and 97% specificity. >This model enables us to detect genotoxic as well as non-genotoxic hepatocarcinogens.
- OSTI ID:
- 21587835
- Journal Information:
- Toxicology and Applied Pharmacology, Vol. 255, Issue 3; Other Information: DOI: 10.1016/j.taap.2011.07.001; PII: S0041-008X(11)00258-4; Copyright (c) 2011 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0041-008X
- Country of Publication:
- United States
- Language:
- English
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