Chromosome damaging activity

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). 

When metabolic activation is used, S9 mix should not exceed 1-10 percent of the culture medium by volume. It has been shown that the S9 mix is clastogenic in CHO cells and mouse lymphoma cells (Cifone et al., 1987 Kirkland et al., 1989) but not in human lymphocytes, where blood components can inactivate active oxygen species which could cause chromosome damage. When S9 mix from animals treated with other enzyme-inducing agents such as phenobarbitone/beta-naphtho-flavone, is used, clastogenesis may be minimized (Kirkland et al., 1989). 

Metaphase Analysis. Metaphase analysis can be performed in any tissue with actively dividing cells, but bone marrow is the tissue most often examined. Cells are treated with a test compound and are arrested in metaphase by the administration of colcemid or colchicine at various sampling times after treatment. Preparations are examined for structural chromosome damage. Because the bone marrow has a good blood supply, the cells should be exposed to the test compound or its metabolites in the peripheral blood supply. Additionally, these cells are sensitive to S-dependent and S-independent mutagens (Topham et al., 1983). 

After metabolic activation, it depoly-merizes DNA and causes chromosomal damage and also nucleic acid synthesis inhibition. It is found to be effective in Hodgkin s disease and carcinoma of lungs. 

Bis(bromomethyl)propane-l,3-diol was mutagenic in only one of several bacterial strains tested, and only with metabolic activation. In cultured mammalian cells, it was only weakly active in tests for chromosomal aberrations and sister chromatid exchanges. Micronucleus formation, indicative of chromosomal damage, was induced in cells from mice exposed to 2,2-bis(bromomethyl)propane-l,3-diol in vivo. 

Methyl acrylate appears to be clastogenic to mammalian cells in vitro. The preferential induction of small colonies rather than large ones in the mouse lymphoma L5178Y tk mutagenicity assay is thought to indicate that mutations arise from chromosomal damage rather than by point mutation. The clastogenic activity of methyl acrylate seen in vitro is not readily detected in vivo. 

The ability of furan to produce chromosome damage in mammalian cells cultured in vitro may be related to the toxicities discussed above as this activity is only evident when rat liver enzymes (S9 mix) are included in the in vitro assay (81MI10502). This is consistent with the enzyme-mediated formation of a DNA-reactive epoxide derivative (cf. Table 2). 

Flaxseed was among the best food sources in the prevention of in vivo spontaneous chromosomal damage in mice (Trentin et al., 2004). The exact reason for the chromosomal damage prevention was not identified however, the mechanism may be related to the antioxidant function of flaxseed components. Lignans have antioxidant activity and thus may contribute to the anticancer activity of flaxseed (Kangas et al., 2002 Kitts et al., 1999 Prasad 1997a, Yuan et al., 1999). 

Similarly, in vitro tests with CHO cells (with activation) caused an increased frequency of chromosome-damaged cells and SCEs and dose-related decreases in colony formations. In a large number of in vitro tests reviewed by Fishein (ref. 184a), diallate was the more active compound of the two. The ultimate mutagen postulated is 2-chlorocrolein formed via a series of sulfoxidation, rearrangement and 1, 2-elimination reactions ... 

A9. Allison, A. C.,.and Patton, G. R., Chromosome damage in human diploid cells following activation of lysosomal enzymes. Nature (London) 207, 1170-1173 (1965). 

Busulfan has been shown to induce gene mutations and chromosomal damage in bacteria, fungi, plant species. Drosophila, and in animal cell lines in culture. Busulfan does not require S9 activation in in vitro toxicity assays. 

Mutagenicity tests with and without metabolic activation have been negative. Testing included Salmonella typhimurium assays, testing in Bacillus sub-tilis, and testing in V79 Chinese hamster cells. In addition, bone marrow evaluated after oral exposure was not reported to contain chromosomal damage. It was not reported to cause dominant lethal mutations in mice at 100 mg kg day... 

DIPE has been tested for genotoxic activity in bacterial mutation assays, a yeast assay for mitotic gene conversion, and in tests using rat liver and Chinese hamster ovary cells with structural chromosome damaging the end point. Negative responses were observed in the bacterial and yeast assays. 

Vanillin was found to directly suppress the in vitro antisheep RBC antibody response at a noncytotoxic dose (200 pg per culture). Vanillin induced chromosomal damage in human cells treated in culture, but showed no genotoxic activity in mice treated orally or in hamster cells in culture. There was also no evidence of mutagenic activity in bacterial (including Ames test) or in yeast. 

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