Sensitive quantitative assay for point mutations in the rat H-ras gene based on single nucleotide primer extension

Yano, Yoshihisa; Yano, Tomohiro; Kinoshita, Anna; Matoba, Ai; Hasuma, Tadayoshi; Wanibuchi, Hideki; Morimura, Keiichirou; Otani, Shuzo; Fukushima, Shoji

doi:10.3892/etm_00000103

Cited by 5 publications

(5 citation statements)

References 21 publications

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“…The values at days 10 and 17 were slightly higher than those of the control group. The control levels of the rat liver BrdU indices detected in the present study at each time point fell into the range of historical background values for data obtained in our laboratory 10 , 11 , 12 . At the start of the experiment on day 3, the BrdU index levels in young rats of both the control and ETBE-treated groups were much higher than those observed in rats at days 10, 17 and 28 ( Table 1 ).…”

Section: Resultssupporting

confidence: 63%

Induction of cell proliferation in the rat liver by the short-term administration of ethyl <i>tertiary</i>-butyl ether

Kakehashi

Hagiwara²,

Imai³

et al. 2015

J Toxicol Pathol

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In the present study, in continuation of our previous experiment in order to investigate the mode of action (MOA) of ethyl tertiary-butyl ether (ETBE) hepatotumorigenicity in rats, we aimed to examine alterations in cell proliferation, that are induced by short-term administration of ETBE. F344 rats were administered ETBE at doses of 0, and 1,000 mg/kg body weight twice a day by gavage for 3, 10, 17 and 28 days. It was found that the previously observed significant increase of P450 total content and hydroxyl radical levels after 7 days of ETBE administration, and 8-OHdG formation at day 14, accompanied by accumulation of CYP2B1/2B2, CYP3A1/3A2, CYP2C6, CYP2E1 and CYP1A1 and downregulation of DNA oxoguanine glycosylase 1, was preceded by induction of cell proliferation at day 3. Furthermore, we observed an increase in regenerative cell proliferation as a result of ETBE treatment at day 28, followed by induction of cell cycle arrest and apoptosis by day 14. These results indicated that short-term administration of ETBE led to a significant early increase in cell proliferation activity associated with induction of oxidative stress, and to a regenerative cell proliferation as an adaptive response, which could contribute to the hepatotumorigenicity of ETBE in rats.

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Section: Resultssupporting

confidence: 63%

Induction of cell proliferation in the rat liver by the short-term administration of ethyl <i>tertiary</i>-butyl ether

Kakehashi

Hagiwara²,

Imai³

et al. 2015

J Toxicol Pathol

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“…Rats exposed to this carcinogen were examined to determine the formation of 1) MeIQx-DNA adducts [105], 2) mutations at the H-ras locus [106] and in LacI transgenes [107], 3) pre-neoplastic lesions (PNL) in the form of GST-positive foci [105], and 4) hepatocellular adenomas and carcinomas [108]. These endpoints were evaluated at 4, 16, 16-32 and 56 weeks of repeat dosing, respectively.…”

Section: Appendix 1 Analysis Of the Relationships Among Pods For Carmentioning

confidence: 99%

IWGT report on quantitative approaches to genotoxicity risk assessment II. Use of point-of-departure (PoD) metrics in defining acceptable exposure limits and assessing human risk

MacGregor¹,

Frötschl

White

et al. 2015

Mutation Research/Genetic Toxicology and Environmental Mutagene

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This is the second of two reports from the International Workshops on Genotoxicity Testing (IWGT) Working Group on Quantitative Approaches to Genetic Toxicology Risk Assessment (the QWG). The first report summarized the discussions and recommendations of the QWG related to the need for quantitative dose-response analysis of genetic toxicology data, the existence and appropriate evaluation of threshold responses, and methods to analyze exposure-response relationships and derive points of departure (PoDs) from which acceptable exposure levels could be determined. This report summarizes the QWG discussions and recommendations regarding appropriate approaches to evaluate exposure-related risks of genotoxic damage, including extrapolation below identified PoDs and across test systems and species. Recommendations include the selection of appropriate genetic endpoints and target tissues, uncertainty factors and extrapolation methods to be considered, the importance and use of information on mode of action, toxicokinetics, metabolism, and exposure biomarkers when using quantitative exposure-response data to determine acceptable exposure levels in human populations or to assess the risk associated with known or anticipated exposures. The empirical relationship between genetic damage (mutation and chromosomal aberration) and cancer in animal models was also examined. It was concluded that there is a general correlation between cancer induction and mutagenic and/or clastogenic damage for agents thought to act via a genotoxic mechanism, but that the correlation is limited due to an inadequate number of cases in which mutation and cancer can be compared at a sufficient number of doses in the same target tissues of the same species and strain exposed under directly comparable routes and experimental protocols.

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“…After the 1-week application of MeIQx in the diet at wide range of doses, H-ras mutation frequency detected by TCEL assay in the rat livers of all groups receiving from 0.001 ppm to 100 ppm dose of MeIQx did not differ from the control value. On the other hand, in the livers of rats treated for 2 weeks, H-ras mutation frequency was elevated in dose-dependent manner, particularly in 10 ppm and 100 ppm MeIQx groups with statistical significance [19].…”

Section: Hepatocarcinogenicity and Mutagenicity Of 2-amino-38-dimethmentioning

confidence: 86%

“…Similarly, the mutation level of H-ras gene, which role in rat hepatocarcinogenesis is not clear, was significantly increased in the livers of rats administered MeIQx at doses higher than 1 ppm (Table 1) [19]. After the 1-week application of MeIQx in the diet at wide range of doses, H-ras mutation frequency detected by TCEL assay in the rat livers of all groups receiving from 0.001 ppm to 100 ppm dose of MeIQx did not differ from the control value.…”

Section: Hepatocarcinogenicity and Mutagenicity Of 2-amino-38-dimethmentioning

confidence: 97%

Threshold in Carcinogenicity of Genotoxic Carcinogens

Kakehashi

Fukushima²,

Wei³

et al. 2014

J Carcinog Mutagen

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Nowadays the idea of threshold in the carcinogenicity of chemical carcinogens has attracted interest in the field of carcinogenesis. With genotoxic agents there is considerable experimental evidence in support of the idea. Here, we report on the low dose carcinogenicity in rats observed with heterocyclic amines contained in cooked food, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and 2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine (PhIP), and contaminants of natural and manufactured food products, N-nitrosocompounds such as N-nitrosodiethylamine (DEN) and N-nitrosodimethylamine (DMN). The existence of a no-effect level for MeIQx carcinogenicity was confirmed in a medium-term rat liver bioassay. Treatment with increasing doses of MeIQx caused sequence of events to occur in the liver tissue: first, the induction of DNA-MeIQx adducts at low doses, then an increase of DNA 8-hydroxy-2'-deoxyguanosine (8-OHdG) formation and lacI gene mutations, following by the development of preneoplastic lesions, glutathione S-transferase placental form positive (GST-P +) foci, at high doses. In another study, IQ was found to induce preneoplastic lesions in the rat liver at high doses, but lack any effect at low doses. Similarly, examination of carcinogenicity of a well-known colon genotoxic carcinogen PhIP have shown that application at low doses caused the formation of PhIP-DNA adducts, however, a surrogate marker of preneoplastic lesions in the colon, aberrant crypt foci, were detected only at high doses. In studies with N-nitrosocompounds, no GST-P+ foci in the rat livers was detected after the treatment at low doses, on the contrary, at high doses DEN and DMN induced their development. In conclusion, DNA-reactive genotoxic agents such as heterocyclic amines MeIQx, IQ and PhIP, and N-nitrosocompounds DEN and DMN were concluded to exert a threshold, at least practical, with respect to their carcinogenicity.

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Sensitive quantitative assay for point mutations in the rat H-ras gene based on single nucleotide primer extension

Cited by 5 publications

References 21 publications

Induction of cell proliferation in the rat liver by the short-term administration of ethyl <i>tertiary</i>-butyl ether

Induction of cell proliferation in the rat liver by the short-term administration of ethyl <i>tertiary</i>-butyl ether

IWGT report on quantitative approaches to genotoxicity risk assessment II. Use of point-of-departure (PoD) metrics in defining acceptable exposure limits and assessing human risk

Threshold in Carcinogenicity of Genotoxic Carcinogens

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