Mutagen screening by a simplified bacterial fluctuation test: Use of microsomal preparations and whole liver cells for metabolic activation

Green, M.H.L.; Bridges, B.A.; Rogers, Alix; Horspool, G.; Muriel, W.J.; Bridges, James W.; Fry, Jeffrey R.

doi:10.1016/0027-5107(77)90171-3

Cited by 97 publications

(14 citation statements)

References 7 publications

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“…These results are in agreement with those of some bacterial mutagenicity tests that showed that rat microsomes and hepatocytes have almost the same capacities to activate DMBA [Green et al, 1977;Bos et al, 1983;Glatt et al, 19841. Experiments with the second reference mutagen, the mycotoxin AFBl, also revealed some SCE-inducing activity without external activation. In V79 cells, this effect was more pronounced than in human lymphocytes.…”

Section: Discussionsupporting

confidence: 94%

Comparison of S9 mix and hepatocytes as external metabolizing systems in Mammalian cell cultures: Cytogenetic effects of 7,12‐dimethylbenzanthracene and aflatoxin B1

et al. 1986

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Two external metabolizing systems, S9 mix from Aroclor-induced rat livers and freshly isolated hepatocytes, were used for activation in cultures of human lymphocytes and V79 cells. 7, 12-dimethylbenzanthracene (DMBA) and aflatoxin B1 (AFB1) were employed as indirectly acting reference mutagens. Mutagenic effects were measured by induction of sister chromatid exchange (SCE). With DMBA, SCE-inducing effects were found to be quite similar after activation by S9 mix and activation by hepatocytes. In human lymphocytes nearly the same dose-effect relationships were found with both metabolizing systems; in V79 cells the hepatocyte-mediated induction of SCE was detectable at slightly lower concentrations than the S9-mediated SCE induction. In contrast with AFB1, S9 activation led to a stronger SCE induction than hepatocyte activation in both target cells. The induction of chromosomal aberrations by AFB1 after activation by the two metabolizing systems was also analysed in V79 cells. This experiment again revealed that AFB1 was more efficiently activated by S9 mix than by hepatocytes, and it appeared that AFB1 is a more potent inducer of chromosomal aberrations than of SCE. The different activation capacities of the two metabolizing systems for AFB1 may be due to the maintenance of inactivation mechanisms in hepatocytes or to the Aroclor induction of the S9 fraction. Our experiments have shown that the suitability of hepatocytes as an activation system is not restricted to microbial or eukaryotic point mutation assays, but that hepatocyte metabolism can also be successfully included in cytogenetic tests with short- and long-term cultures of mammalian target cells.

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Section: Discussionsupporting

confidence: 94%

Comparison of S9 mix and hepatocytes as external metabolizing systems in Mammalian cell cultures: Cytogenetic effects of 7,12‐dimethylbenzanthracene and aflatoxin B1

et al. 1986

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“…This supports the previous demonstrations that HPCs can mediate mutagenesis at the HGPRT locus in an established rat liver epithelial line [San and Williams, 19771 and recently, in a human cell line [Tong et al, 19811. These findings, as well as others [Bermudez et al, 1980;Green et al, 1977;Probst et al, 19801 differ from the observations of Langenbach et a1 [1978] who reported that rat hepatocytes did not activate benzo(a)pyrene to a mutagenic metabolite and suggested that this reflected the tissue specificity for the action of PAH. Rather, our findings correlate with metabolism studies [Schmeltz et al, 19781 and clearly indicate that rat liver cell cultures do retain their intrinsic metabolic capability for biotransformation of PAH.…”

Section: Discussioncontrasting

confidence: 81%

The use of adult rat liver cultures in the detection of the genotoxicity of various polycyclic aromatic hydrocarbons

et al. 1981

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The hepatocyte primary culture (HPC)--DNA repair test and the adult rat liver epithelial cell (ARL)--hypoxanthine-guanine phosphoribosyl transferase (HGPRT) mutagenesis assay are two in vitro short-term tests that possess intrinsic capability for xenobiotic biotransformation. Both assays detected the genotoxicity of a variety of carcinogenic polycyclic aromatic hydrocarbons. Thus, these two tests, which embody intact cellular metabolism, are useful for the evaluation of this class of carcinogens and provide results that strengthen those obtained in tests dependent upon subcellular metabolism.

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“…Over the years, this recognition for the Salmonella assay resulted in a plethora of modifications that have enabled the assay to be used in an almost infinite variety of ways. These include modifications permitting a ) the use of small amounts of sample (Diehl et al 2000; Flamand et al 2001; Green et al 1977; Houk et al 1989; Kado et al 1983) in semi–high-throughput modes involving colorimetric analysis (Kamber et al 2009; Umbuzeiro et al 2010) and fluorescent assays (Aubrecht et al 2007; Cariello et al 1998); b ) the testing of volatiles and gases (Baden et al 1976; Hughes et al 1987); c ) the testing of body fluids, including urine (Cerná and Pastorková 2002), feces (de Kok and van Maanen 2000), breast milk (Phillips et al 2002; Thompson et al 2002), breast nipple aspirates (Klein et al 2001), and cervical mucus (Holly et al 1993); d ) the testing of all types of complex mixtures, including air, soil, water, house dust, and combustion emissions (see “Paradigm Shift II” above), and fried meat (Knize and Felton 2005); e ) molecular (DeMarini 2000; Koch et al 1994) and genomic analyses (Porwollik et al 2001; Ward et al 2010); and f ) the evaluation of mutagenicity inside the International Space Station (Rabbow et al 2003). This flexibility has permitted the Salmonella assay to be used for almost every conceivable type of environmental and molecular epidemiology study.…”

Section: The Salmonella Assay As a Model For 21st Century Toxicology mentioning

confidence: 99%

TheSalmonellaMutagenicity Assay: The Stethoscope of Genetic Toxicology for the 21st Century

Claxton

Umbuzeiro

DeMarini

2010

Environ Health Perspect

133

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ObjectivesAccording to the 2007 National Research Council report Toxicology for the Twenty-First Century, modern methods (e.g., “omics,” in vitro assays, high-throughput testing, computational methods) will lead to the emergence of a new approach to toxicology. The Salmonella mammalian microsome mutagenicity assay has been central to the field of genetic toxicology since the 1970s. Here we document the paradigm shifts engendered by the assay, the validation and applications of the assay, and how the assay is a model for future in vitro toxicology assays.Data sourcesWe searched PubMed, Scopus, and Web of Knowledge using key words relevant to the Salmonella assay and additional genotoxicity assays.Data extractionWe merged the citations, removing duplicates, and categorized the papers by year and topic.Data synthesisThe Salmonella assay led to two paradigm shifts: that some carcinogens were mutagens and that some environmental samples (e.g., air, water, soil, food, combustion emissions) were mutagenic. Although there are > 10,000 publications on the Salmonella assay, covering tens of thousands of agents, data on even more agents probably exist in unpublished form, largely as proprietary studies by industry. The Salmonella assay is a model for the development of 21st century in vitro toxicology assays in terms of the establishment of standard procedures, ability to test various agents, transferability across laboratories, validation and testing, and structure–activity analysis.ConclusionsSimilar to a stethoscope as a first-line, inexpensive tool in medicine, the Salmonella assay can serve a similar, indispensable role in the foreseeable future of 21st century toxicology.

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Mutagen screening by a simplified bacterial fluctuation test: Use of microsomal preparations and whole liver cells for metabolic activation

Cited by 97 publications

References 7 publications

Comparison of S9 mix and hepatocytes as external metabolizing systems in Mammalian cell cultures: Cytogenetic effects of 7,12‐dimethylbenzanthracene and aflatoxin B1

Comparison of S9 mix and hepatocytes as external metabolizing systems in Mammalian cell cultures: Cytogenetic effects of 7,12‐dimethylbenzanthracene and aflatoxin B1

The use of adult rat liver cultures in the detection of the genotoxicity of various polycyclic aromatic hydrocarbons

TheSalmonellaMutagenicity Assay: The Stethoscope of Genetic Toxicology for the 21st Century

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