Evaluation of pyrazole and ethanol induced S9 fraction in bacterial mutagenicity testing

Burke, Dave; Wedd, D.J.; Herriott, Donald E.; Bayliss, Martin K.; Spalding, David J.; Wilcox, Philip E.

doi:10.1093/mutage/9.1.23

Cited by 29 publications

(12 citation statements)

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“…It is known that the metabolism of urethane is a critical issue in detecting its activity. This was studied by Burke et al [16], who were unable to detect any mutagenic responses with urethane in 6 strains of Salmonella and 2 strains of E. coli using several different inducers of rat S9 (Aroclor-1254, phenobarbitone/␤-naphthoflavone, pyrazole and ethanol), the latter designed to increase CYP2E1 levels. Urethane is included in the database with an overall Ames test call of E. It therefore would not have been included in this analysis if E results were considered as negative.…”

Section: Discussion Of Negative In Vitro Results With Carcinogens Andmentioning

confidence: 99%

Can in vitro mammalian cell genotoxicity test results be used to complement positive results in the Ames test and help predict carcinogenic or in vivo genotoxic activity? II. Construction and analysis of a consolidated database

Kirkland¹,

Zeiger²,

Madia

et al. 2014

Mutation Research/Genetic Toxicology and Environmental Mutagene

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A Workshop sponsored by EURL ECVAM was held in Ispra, Italy in 2013 to consider whether the in vitro mammalian cell genotoxicity test results could complement and mitigate the implications of a positive Ames test response for the prediction of in vivo genotoxicity and carcinogenicity, and if patterns of results could be identified. Databases of Ames-positive chemicals that were tested for in vivo genotoxicity and/or carcinogenicity were collected from different sources and analysed individually (Kirkland et al., in this issue). Because there were overlaps and inconsistent test results among chemicals in the different databases, a combined database which eliminated the overlaps and evaluated the inconsistencies was considered preferable for addressing the above question. A database of >700 Ames-positive chemicals also tested in vivo was compiled, and the results in in vitro mammalian cell tests were analysed. Because the database was limited to Ames-positive chemicals, the majority (>85%) of carcinogens (103/119) and in vivo genotoxins (83/88) were positive when tested in both in vitro gene mutation and aneugenicity/clastogenicity tests. However, about half (>45%) of chemicals that were not carcinogenic (19/28) or genotoxic in vivo (33/73) also gave the same patterns of positive mammalian cell results. Although the different frequencies were statistically significant, positive results in 2 in vitro mammalian cell tests did not, per se, add to the predictivity of the positive Ames test. By contrast, negative results for both in vitro mammalian cell endpoints were rare for Ames-positive carcinogens (3/119) and in vivo genotoxins (2/88) but, were significantly more frequent for Ames-positive chemicals that are not carcinogenic (4/28) or genotoxic in vivo (14/73). Thus, in the case of an Ames-positive chemical, negative results in 2 in vitro mammalian cell tests covering both mutation and clastogenicity/aneugenicity endpoints should be considered as indicative of absence of in vivo genotoxic or carcinogenic potential.

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Section: Discussion Of Negative In Vitro Results With Carcinogens Andmentioning

confidence: 99%

Can in vitro mammalian cell genotoxicity test results be used to complement positive results in the Ames test and help predict carcinogenic or in vivo genotoxic activity? II. Construction and analysis of a consolidated database

Kirkland¹,

Zeiger²,

Madia

et al. 2014

Mutation Research/Genetic Toxicology and Environmental Mutagene

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“…For example, in vitro genotoxicity studies on N-nitrosodiphenylamine [CAS: 86±30±6] were inconclusive or negative (McGregor 1994) with the exception of one study, where microcolony induction in S. typhimurium TA104 was observed in the presence of arochlor-1254 induced S9 at pH 6.5 (Zielenska and Guttenplan 1988). The potent experimental carcinogen N-nitrosopyrrolidine (Berger et al 1987) can only be eectively activated to Ames test positive metabolites by pyrazole-induced rat liver S9 (Burke et al 1994). Pyrazole is known to induce CYP2E1 in rat liver.…”

Section: Discussionmentioning

confidence: 99%

Genotoxicity of N -nitrosodicyclohexylamine in V79 cells in the sister chromatid exchange test and the single cell gel assay

et al. 2001

Archives of Toxicology

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Dicyclohexylaminexnitrite is used in chemical formulations as an anti-corrosion agent. N-Nitrosodicyclohexylamine (N-NO-DCHA) can be formed by nitrosation from dicyclohexylamine during the application of these formulations. As most of the nitrosamines are genotoxic carcinogens, the genotoxic potential of N-NO-DCHA was investigated in V79 Chinese hamster cells in the single cell gel assay and the sister chromatid exchange (SCE) test. In addition, N-NO-DCHA cytotoxicity was determined in the neutral red assay. Neutral red uptake was suppressed up to 50% after 24 h incubation at a concentration of approximately 135 microM. In the single cell gel assay, a significantly elevated and dose-dependent induction of DNA lesions was detected in a concentration range from 5 microM to 100 microM (P<0.001). The use of proteinase K (1 mg/ml) in the lysing solution did not influence these results. In the SCE analysis, a significant induction of SCE was found at a minimum concentration of 5 microM N-NO-DCHA as well. A dose-dependent SCE induction could be detected up to the maximum concentration tested in the assay (100 microM). In conclusion, N-NO-DCHA is genotoxic in V79 cells in the single cell gel assay and the SCE test. With respect to human health hazard prevention, a substitution of dicyclohexylaminexnitrite in chemical formulations used to prevent corrosion is recommended.

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“…Reports on the effect of BNF on CYP2E1 are conflicting, but some data indicate that CYP2E1 in rat liver and in cultured rat hepatocytes is suppressed by the combined administration of BNF and phenobarbital [36] or 3MC and phenobarbital [37], respectively. Medaka microsomes also lacked detectable DMN demethylase activity, a marker substrate for CYP2E1.…”

Section: Discussionmentioning

confidence: 99%

Metabolism of Trichloroethylene and Chloral Hydrate by the Japanese Medaka (Oryzias Latipes) in Vitro

Lipscomb¹,

Confer²,

Miller³

et al. 1998

Environ Toxicol Chem

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Trichloroethylene (TRI), a common groundwater contaminant, is readily metabolized by mammals to produce chloral hydrate (CH), trichloroacetic acid (TCA), and trichloroethanol (TCOH). Cytochrome P450 (CYP) and other enzymes are responsible for formation of these metabolites, which are implicated in TRI's toxicity and carcinogenicity. To establish the validity of the Japanese medaka (Oryzias latipes) as an alternate test species for TRI, we examined the metabolism of TRI and CH, as well as CYP expression, in medaka liver preparations. Trichloroethylene was incubated with medaka microsomal protein, and metabolites were extracted and analyzed using gas chromatography. Microsome‐mediated metabolism of TRI was observed, and a Km value for TRI oxidation of 540 μM and a Vmax value of 213 pmol/min·mg−1 protein were obtained. Conversion of TRI to CH, TCA, and TCOH was found with medaka hepatic subcellular fractions. In addition, a sex difference in hepatic microsomal TRI metabolism, specific CYP content, and ethoxyresorufin O‐deethylase activity was noted. The lower specific activity of preparations from the livers of female medaka is compensated for by increased total protein in the larger liver mass of the female. Immunochemical analysis showed that CYP1A was readily detectable in medaka liver, but CYP2E1 was present at very low levels. These data suggest that TRI metabolism in medaka liver preparations mimics that observed in mammalian systems and supports their use as an alternative test species in the evaluation of the toxicity of TRI.

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Evaluation of pyrazole and ethanol induced S9 fraction in bacterial mutagenicity testing

Cited by 29 publications

References 0 publications

Can in vitro mammalian cell genotoxicity test results be used to complement positive results in the Ames test and help predict carcinogenic or in vivo genotoxic activity? II. Construction and analysis of a consolidated database

Can in vitro mammalian cell genotoxicity test results be used to complement positive results in the Ames test and help predict carcinogenic or in vivo genotoxic activity? II. Construction and analysis of a consolidated database

Genotoxicity of N -nitrosodicyclohexylamine in V79 cells in the sister chromatid exchange test and the single cell gel assay

Metabolism of Trichloroethylene and Chloral Hydrate by the Japanese Medaka (Oryzias Latipes) in Vitro

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