Induced mutagenesis

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. 

Guttenplan, J. B., M. Chen, W. Kosinska et al. 2001. Effects of a lycopene-rich diet on spontaneous and benzo[a] pyrene-induced mutagenesis in prostate, colon and lungs of the lacZ mouse. Cancer Lett 164(l) l-6. 

Induced mutagenesis in Escherichia coli is an active process involving proteins with DNA replication, repair, and recombination functions. The available evidence suggests that mutations are generated at sites where DNA has been damaged and that they arise via an error-prone repair activity. In an attempt to understand what specific contributions to mutagenesis are made by DNA lesions, we have studied the mutational specificity of some carcinogens, such as benzo[a]pyrene and aflatoxin, whose chemical reactions with DNA are... 

Yamagishi M, Natsume M, Osakabe N, and others. 2002. Effects of cacao liquor proanthocyanidins on PhlP-induced mutagenesis in vitro, and in vivo mammary and pancreatic tumorigenesis in female Sprague-Dawley rats. Cancer Lett 185(2) 123-130. 

Monomethylhydrazine-induced mutagenesis was not observed in Ames Salmonella/ microsome with activation (Matheson et al. 1978). In vivo tests in mice (dominant lethal, revertants in host-mediated assay), and dogs (micronuclei) were negative (reviewed in Trochimowicz 1994). However, in vitro chromosomal damage in human and rat tissue has been demonstrated, although in vivo liver DNA damage (as determined by DNA alkaline elution) was equivocal (reviewed in Trochimowicz 1994). 

Many plasmids are known to possess three properties (1) increased resistance to the bactericidal effects of UV and chemical mutagens, (2) increased spontaneous mutagenesis, and (3) increased susceptibility to UV and chemically induced mutagenesis. Some plasmids possess all three properties others may possess just one, for example, increased susceptibility to mutagenesis (review Mortelmans and Dousman, 1986). Often the profile of activity depends on the DNA repair status of the host cell (Pinney, 1980). Plasmid pKMIOl carries DNA repair genes and has been widely used in strains used in bacterial mutagenicity tests. 

Fox, M. (1981). Some quantitative aspects of the response of mammalian in vitro to induced mutagenesis. In Cancer Biology Reviews (Marchelonis, J.J. and Hanna, M.G., Eds.). Vol. 3, Marcel Dekker, New York, pp. 23-62. 

Villani, G., Boiteux, S. and Radman, M. (1978). Mechanisms of ultraviolet-induced mutagenesis extent and fidelity of in vitro DNA synthesis on irradiated template. Proc. Nat. Acad. Sci. USA 75 3037-3041. 

Control of spontaneous and damage-induced mutagenesis by SUMO and ubiquitin conjugation. Nature 2003, 425, 188-91. 

Foster PL (2007) Stress-induced mutagenesis in bacteria. Crit Rev Biochem Mol Biol... 

Ubc2/Rad6 20 DNA repair, induced mutagenesis, sporulation, repression of retrotransposition, N-end ruie pathway... 

Hartwig A, Beyersmann D. 1989. Enhancement of UV-induced mutagenesis and sister-chromatid exchanges by nickel ions in V79 cells Evidence for inhibition of DNA repair. Mutat Res 217 65-73. 

Z-aminO 1 -methy 1 6 phenylimidazo [4,5-b]-pyridine 2 aminO 3,7,8 trimethylimidazo[4,5 f]quinoxaline 2 aminO 3,4,7,8 tetramethyl 3H imidazO [4,5 f]quinoxaline inoxaline 3 aminO l,4 dimethyl SH pyrid [4,3 b] indole (Trp P I) and 3 aminO l methyl 5H pyrido [4,3 b]indole induced mutagenesis. Metabolic activation was required for positive results b... 

Antimutagenic activity. Water extract of the dried gum, on agar plate at a concentration of 2 mg/plate, was inactive on SalmO nella typhimurium TAIOO vs aflatoxin Bl-induced mutagenesis and a concentration of 10 mg/plate, was inactive on SalmO nella typhimurium TA98 " . Asafoetida, on agar plate at a dose of 0.5 (Xg/plate was active on Salmonella typhimurium TA98 and... 

TAIOO vs aflatoxin Bl-induced mutagenesis " . Asafoetida, on agar plate, was active on Salmonella typhimurium TAIOO and TA1535 microsomal activation-depen-dent mutagenicity of 2-acetamidofluo-rene """. 

Antimutagenic activity. Ethanol (70%) extract of the dried aerial parts, on agar plate, was inactive on Escherichia coli PQ37 vs mitomycin-induced mutagenesis, assessed by the SOS-chromotest method Antioxidant activity. Hexane and methanol extracts of the dried seed, tested on lard at a concentration of 0.06 %, were inactive Seed oil, at undiluted concentration, was active " . Acetone extract of the seed, at a concentration of 0.2 mg/kg, was active. Linoleic acid was used as a substrate in this test " . 

Seed, J. L K. G. Specht, T. A. Dahl, and W. R. Midden, Singlet Oxygen Induced Mutagenesis of Benzo[tf]pyrenc Derivatives, Photochem. Photobiol., 50, 625-632 (1989). 

Goth-Goldstein, R. and Burki, H.J. (1980). Ethylnitrosourea-induced mutagenesis in asynchronous and synchronous Chinese hamster ovary cells, Mutat. Res. 69,127. 

Rossman TG, Molina M. 1986. The genetic toxicology of metal compounds II. Enchancement of ultraviolet light-induced mutagenesis in Escherichia coli WP2. Environ Mutagen 8 263-271. 

Enhancement of Mutagenicity by Retinol or Retinyl Acetate. We initially examined the effect of vitamin A alcohol (retinol) on 2-fluorenamine-induced mutagenesis in S. typhimurium (TA98) (23). 

Table I. Dependence upon carcinogen activator source of 2-FA-induced mutagenesis in J5. typhimurium...

Table II. Modification of 2-FA-induced mutagenesis in S. typhimurium TA98 by retinol utilizing carcinogen activation sources prepared from rats not treated with polychlorinated biphenyls...

Figure 2. Inhibition of microsome-mediated 2-fluorenamine (2-FA)-induced mutagenesis in S. typhimurium (TA98) by retinyl acetate. Horizontal dashed line shows average number of spontaneous his+ revertants per plate. Open bars - l.Opg 2-FA/plate cross-hatched bars - 0.5Mg 2-FA/plate solid bars - 0.25pg 2-FA/plate.

Table VI. Effect of retinol, 13-cis-retinoic acid and 3-carotene on 2-FA-induced mutagenesis in . typhimurium (TA98) mediated by purified microsomes...

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