Ames positive mutagens

Nitrenium ions formed from a large number of known drugs and Ames positive mutagens were analysed by DFT theory. The lack of a correlation with mutagenicity led to the conclusion that other physical properties besides nitrenium ion stability are important determinants. In a similar paper, energies of the nitrenium ions derived from thousands of commercially available amines were calculated. Contrary to above, the... 

Benzyl chloride induced a positive mutagenic response ia the Ames Assay ia strain TA 100 with and without rat Hver S-9 metaboHc activation. 

Figure 8.8 Scaffold (cyclohexene) hierarchy derived from mutagenicity dataP8] The proportion of Ames negative to Ames positive counts is qualitatively indicated below each scaffold. The confidence interval of the proportions is shown on the right of the scaffolds. Data taken from Kho et al.[3 I...

The application of several short-term tests to detect carcinogenic hydrazine derivatives has been of limited success 204a, 260). While a host-mediated assay of 1,2-dimethylhydrazine has been reported to give a positive mutagenic response in S. typhimurium G46 345a), the Ames assay has generally not been sensitive toward this class of compounds. In view of the limited reports on the successful applications of an in vitro metabolic activation system for these compounds, comparisons of such methods are not valid at this time. 

Diisopropyl- amine Mutagenicity negative, Ames [107] Mutagenicity questionably positive, Ames, 1 tg per plate [102, 108] DNA repair negative, rat hepatocyte primary culture assay [104] Guinea pig sensitizer, negative [104]... 

The Ames test involves the reversion from a his— to his+ phenotype in any one of multiple bacterial strains (usually five strains are tested simultaneously). If the addition of test compound to a his— strain of bacteria allows them to grow on histidine deficient media, the obvious conclusion is compound-induced mutagenesis and a high potential hazard for the compound being carcinogenic. This test can also be conducted in the presence or absence of metabolic activation, in order to provide more information on potential risks (i.e., the parent compound may not be mutagenic, but the primary metabolite may present a safety risk). In practice, a positive Ames test almost always leads to discontinuing work on a compound of interest, and so these data are always collected prior to nomination of a compound for development. 

The Ames salmonella-microsome test is a principal sensitive mutagen screening test. Compounds are tested on the mutants of Salmonella typhimurium for reversion from a histidine requirement back to prototrophy. A positive result is seen by the growth of revertant bacteria (which do not require an external histidine source). A microsomal activation system should be included in this assay. The use of five different bacterial test strains are generally required. 

Before administration of a NME to man, a mutagenicity test in bacterial cells (Ames test), with and without metabolic activation, and tests for chromosomal aberrations in mammalian cells should be negative. Any positive or equivocal results will require additional tests to be performed before proceeding to man. Studies of embryo-foetal toxicity should be performed before administration of a NME to women of reproductive potential. Studies of fertility, early embryonic development and pre- and post-natal development are not required at this stage of development neither are carcinogenicity studies. 

A study of the mutagenicity of ZDC used a battery of in vitro mutagenicity studies. ZDMC and ZDEC were positive in both the Ames Salmonella lyphimurium assay and the human lymphoqnie cell mutation assay but not in the mouse lymphoma cell mutation assay. In contrast, ZDBC was not positive in the assays. 

To determine the mutagenic potential of nonaqueous liquids as measured by the Ames SaZmoneZ/a/mammalian-enzyme assay, the following protocol is recommended for the sample preparation. In step 1, the desiccator assay is performed on the neat material. The desiccator assay allows the detection of volatile mutagens (such as chlorinated solvents) that are often missed in the plate incorporation and pre-in-cubation assays (16, 17). In addition, a suspension of the neat material (20 mg/mL) is prepared by ultrasonication (5 min at room temperature) in high-purity DMSO (18, 19) and tested in the normal plate incorporation assay as well as in a pre-incubation Ames assay (20). The pre-in-cubation assay allows the detection of certain mutagens, such as dimethylnitrosamine, that require additional time for activation by mammalian or bacterial enzymes. A positive response in any of these three assays indicates the presence of mutagenic components, and the evaluation process is completed. 

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