Dammar resin, a non-mutagen, inducts oxidative stress and metabolic enzymes in the liver of gpt delta transgenic mouse which is different from a mutagen, 2-amino-3-methylimidazo[4,5-f]quinoline

Xie, Xing; Wei, Min; Kakehashi, Anna; Yamano, Shotaro; Okabe, Kyoko; Tajiri, Masaki; Wanibuchi, Hideki

doi:10.1016/j.mrgentox.2012.06.005

Cited by 8 publications

(11 citation statements)

References 44 publications

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“…A significant increase in the MFs of the gpt genes in the rats treated with 2-AAF, IQ and SF was shown using the GPG46 model. Spectrum analysis in the gpt mutant colonies revealed that guanine-related mutations and single base pair deletions were induced by 2-AAF and IQ, but not SF, which is in agreement with previous reports 35 , 36 , 37 . In the conventional medium-term bioassay, 2-AAF, IQ and SF exposure induced a marked increase in the development of GST-P-positive foci 38 , implying that these chemicals also exert a strong tumor promoting action.…”

Section: Discussionsupporting

confidence: 92%

Development of a Medium-term Animal Model Using <i>gpt</i> Delta Rats to Evaluate Chemical Carcinogenicity and Genotoxicity

et al. 2013

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In this study, the potential for development of an animal model (GPG46) capable of rapidly detecting chemical carcinogenicity and the underlying mechanisms of action were examined in gpt delta rats using a reporter gene assay to detect mutations and a medium-term rat liver bioassay to detect tumor promotion. The tentative protocol for the GPG46 model was developed based on the results of dose-response exposure to diethylnitrosamine (DEN) and treatment with phenobarbital over time following DEN administration. Briefly, gpt delta rats were exposed to various chemicals for 4 weeks, followed by a partial hepatectomy (PH) to collect samples for an in vivo mutation assay. The mutant frequencies (MFs) of the reporter genes were examined as an indication of tumor initiation. A single intraperitoneal (ip) injection of 10 mg/kg DEN was administered to rats 18 h after the PH to initiate hepatocytes. Tumor-promoting activity was evaluated based on the development of glutathione S-transferase placental form (GST-P)-positive foci at week 10. The genotoxic carcinogens 2-acetylaminofluorene (2-AAF), 2-amino-3-methylimidazo [4,5-f] quinolone (IQ) and safrole (SF), the non-genotoxic carcinogens piperonyl butoxide (PBO) and phenytoin (PHE), the non-carcinogen acetaminophen (APAP) and the genotoxic non-hepatocarcinogen aristolochic acid (AA) were tested to validate the GPG46 model. The validation results indicate that the GPG46 model could be a powerful tool in understanding chemical carcinogenesis and provide valuable information regarding human risk hazards.

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Section: Discussionsupporting

confidence: 92%

Development of a Medium-term Animal Model Using <i>gpt</i> Delta Rats to Evaluate Chemical Carcinogenicity and Genotoxicity

et al. 2013

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“…However, a lack of in vivo mutagenicity and increased CYPs and 8-OHdG levels in the liver were reported in gpt delta mice (Xie et al, 2012). Although other additional data sets are required to confirm the robustness of classifier, our constructed prediction model might be applicable to new data sets.…”

Section: Construction and Test Of Classifier For Detecting Ngtx Hepatmentioning

confidence: 87%

“…Eighteen compounds had reported hepatocarcinogenicity in rats, of which 13 (AAA, CCL4, CFB, CMA, EE, ETN, GFZ, HCB, MCT, MP, PB, TAA, and WY) were negative for mutagenicity based on information from GENETOX or other manuscripts (Gonzalez et al, 1998;Kirkland et al, 2005;Müller-Tegethoff et al, 1995;Ohta, 1993;Schiestl and Reddy, 1990) and were defined as NGTX hepatocarcinogens in this study (Table 1). In addition, given that DAM and PBO were reported as NGTX hepatocarcinogens when used in external data sets (Okamiya et al, 1998;Xie et al, 2012), these compounds were defined as NGTX hepatocarcinogens in the present study ( (Kirkland et al, 2005;Wozniak et al, 2007) and were defined as GTX hepatocarcinogens. Forty-two compounds had no hepatocarcinogenicity and were defined as non-hepatocarcinogens (Table 2).…”

Section: Selection Of Ngtx Hepatocarcinogens and Non-hepatocarcinogensmentioning

confidence: 99%

Detection of non-genotoxic hepatocarcinogens and prediction of their mechanism of action in rats using gene marker sets

Kanki

Fujioka

et al. 2016

J. Toxicol. Sci.

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-Several studies have successfully detected hepatocarcinogenicity in rats based on gene expression data. However, prediction of hepatocarcinogens with certain mechanisms of action (MOAs), such as enzyme inducers and peroxisome proliferator-activated receptor α (PPARα) agonists, can prove difficult using a single model and requires a highly toxic dose. Here, we constructed a model for detecting non-genotoxic (NGTX) hepatocarcinogens and predicted their MOAs in rats. Gene expression data deposited in the Open Toxicogenomics Project-Genomics Assisted Toxicity Evaluation System (TG-GATEs) was used to investigate gene marker sets. Principal component analysis (PCA) was applied to discriminate different MOAs, and a support vector machine algorithm was applied to construct the prediction model. This approach identified 106 probe sets as gene marker sets for PCA and enabled the prediction model to be constructed. In PCA, NGTX hepatocarcinogens were classified as follows based on their MOAs: cytotoxicants, PPARα agonists, or enzyme inducers. The prediction model detected hepatocarcinogenicity with an accuracy of more than 90% in 14-and 28-day repeated-dose studies. In addition, the doses capable of predicting NGTX hepatocarcinogenicity were close to those required in rat carcinogenicity assays. In conclusion, our PCA and prediction model using gene marker sets will help assess the risk of hepatocarcinogenicity in humans based on MOAs and reduce the number of two-year rodent bioassays.

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“…The assay was conducted according to previously published methods (Xie et al, 2012b). All the confirmed gpt mutants recovered from the urinary bladder mucosa were sequenced; identical mutations from the same rat were counted as one mutant.…”

Section: Gpt Mutation Assaymentioning

confidence: 99%

“…The SpiÀ assay was conducted according to previously published methods (Xie et al, 2012b). Packaged phages were incubated with E. coli XL-1 Blue MRA for survival titration and E. coli XL-1 Blue MRA P2 for mutant selection.…”

Section: Spià Assaymentioning

confidence: 99%

Ethanol-extracted propolis enhances BBN-initiated urinary bladder carcinogenesis via non-mutagenic mechanisms in rats

Xie

Fujioka

et al. 2015

Food and Chemical Toxicology

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Dammar resin, a non-mutagen, inducts oxidative stress and metabolic enzymes in the liver of gpt delta transgenic mouse which is different from a mutagen, 2-amino-3-methylimidazo[4,5-f]quinoline

Cited by 8 publications

References 44 publications

Development of a Medium-term Animal Model Using <i>gpt</i> Delta Rats to Evaluate Chemical Carcinogenicity and Genotoxicity

Development of a Medium-term Animal Model Using <i>gpt</i> Delta Rats to Evaluate Chemical Carcinogenicity and Genotoxicity

Detection of non-genotoxic hepatocarcinogens and prediction of their mechanism of action in rats using gene marker sets

Ethanol-extracted propolis enhances BBN-initiated urinary bladder carcinogenesis via non-mutagenic mechanisms in rats

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