Bacterial Mutagenicity

McCann, J., Spingam, N.-E., Kobori, J. and Ames, B.N. (1975b). Detection of carcinogens as mutagens Bacterial tester strains with R factor plasmids. Proc. Natl. Acad. Sci. USA 72 979-983. 

XXVIII), and dibenzo[ a, e]pyrene (XXX) are 24, 6.9, and 2.9 times more mutagenic in this human cell assay than BaP (Durant et al., 1996). Dibenzo[a,/]pyrene is nearly 50 times more powerful than BaP in the MCL-5 human cell assay (see Busby and co-workers (1995) for a discussion of its mutagenicity, bacterial and human cell, and animal carcinogenicity). 

Levin D-E, Hollstein M, Christman M-F, Schwiers E-A and Ames B-N (1982) A new Salmonella tester strain with A.T base pairs at the site of mutation detects oxidative mutagens. Proc Nad Acad Sci USA 79 7445-7449 Maron D-M, Ames B-N (1983) Revised methods for the Salmonella mutagenicity test. Mutation Res 113 173-215 McCann J, Springarn N-E, Kobory J and Ames B-N (1975) Detection of carcinogens as mutagens bacterial tester strains with R factor plasmids. Proc Nat Acad Sci USA 72 979-983... 

Mutagenicity—bacterial reporter gene assay (SOS repair system) and DEREK (in Silico)... 

Mutagenicity. The AJ-nitrosamines, in general, induce mutations in standard bacterial-tester strains (117). As with carcinogenicity, enzymatic activation, typically with Hver microsomal preparations, is required. Certain substituted A/-nitrosamine derivatives (12) induce mutations without microsomal activation (31,33,34). Because the a-acetoxy derivatives can hydroly2e to the corresponding a-hydroxy compounds, this is consistent with the hypothesis that enzymatic oxidation leads to the formation of such unstable a-hydroxy intermediates (13) (118). However, for simple /V-nitrosamines, no systematic relationship has been found between carcinogenicity and mutagenicity (117,119—123). 

Vanillin has been reported to be a bio antimutagen, demonstrating the abiUty to protect against mutagenic effects by enhancement of an error-free post-rephcation repair pathway. Vanillin has been reported to be nonmutagenic in bacterial systems, but conflicting results in mammalian systems leave no clear indication of the SCE-inducing potential of vanillin. 

Moriya M, Ohta T, Watanabe K, et al. 1983. Eurther mutagenicity studies on pesticides in bacterial reversion assay systems. Mutat Res 116 185-216. 

Dekant W, Vamvakas S, Berthold K, et al. 1986c. Bacterial P-lyase mediated cleavage and mutagenicity of cysteine conjugates derived from the nephrocarcinogenic alkenes trichloroethylene, tetrachloroethylene, and hexachlorobutadiene. Chem Biol Interact 60 31-45. 

It appears that considerable metabolism of nitrosamines takes place in the liver, from the finding that most of them are activated by rat liver microsomes to bacterial mutagens. However, relatively few nitrosamines induce liver tumors in rats. The most common target is the esophagus and a wide variety of nitrosamines induce tumors in this organ of rats, some only tumors of the esophagus, others tumors of other organs also. 

The experiments with deuterium-labeled nitrosamines illustrate two important points. One is that oxidation of nitrosamines takes place at more than one position in the molecule, and the outcome of the balance of such competing reactions probably is the determinant of carcinogenic potency. The second is that the reason for the failure of carcinogenesis to be mirrored in many cases by the microsomally activated bacterial mutagenicity is that there can be several metabolic steps leading to formation of the proximate carcinogenic agent and not all of these need necessarily involve microsomal enzymes. ... 

Enya T, H Suzuki, T Watanabe, T Hiurayama, Y Hisamatsu (1997) 3-nitrobenzanthrone, a powerful bacterial mutagen and suspected human carcinogen found in diesel exhaust and airborne particulates. Environ Sci Technol 31 2772-2776. 

Sayama M, M Inoue, M-A Mori, Y Maruyama, H Kozuka (1992) Bacterial metabolism of 2,6-dinitrotoluene with Salmonella typhimurium and mutagenicity of the metabolites of 2,6- dinitrotoluene and related compounds. Xenobiotica 22 633-640. 

Why is it important to understand the mechanism of DNA damage by oxidative stress Oxidative stress, imposed by a variety of mechanisms (including increased O2 concentrations) has been convincingly shown to be mutagenic to bacterial and mammalian cells (reviewed by Halliwell and Aruoma, 1991 see also, Essigmann and... 

Quercetin is a naturally occurring flavonoid with both antioxidant and prooxidant activities (Scheme 10.12).90 It has been demonstrated in a variety of bacterial and mammalian mutagenicity experiments that quercetin has mutagenic properties that could be related to quinoid formation.91,92 Quercetin is initially oxidized to an o-quinone, which rapidly isomerizes to di-QMs that could also be called extended... 

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. 

DMBA trans-3.4-dihvdrodiol is a metabolite of DMBA (34) and a potent mutagen to cultured bacterial (35.36) and mammalian cells (37.38) as well as a potent tumorigen (39.40). 

Recent advances in PAH carcinogenesis research over the past decade have led to identification of diol epoxide metabolites as the principal active forms of the PAH investigated to date Q,2). Benzo-(a)pyrene (BP) has been most intensively investigated, and it has been demonstrated that a diol epoxide metabolite anti-BPDE is the active intermediate which binds covalently to DNA in human and other mammalian tissues 0,4). Anti-BPDE was also demonstrated to be a powerful mutagen in both bacterial and mammalian cells (15) These findings stimulated an outpouring of research directed towards elucidation of the molecular mechanism of PAH carcinogenesis. 

McCann et al. (67) had shown that benzo[a]pyrene was mutagenic for j>. typhimurium only if the bacteria carried the mutation enhancing plasmid pKMIOl whose activity was later shown by Walker (23) to be entirely dependent on bacterial recA and lexA controlled functions. 

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