Mutagenesis Rossman

The lack of mutagenicity by metal compounds in bacterial assays may be due to a number of factors (Rossman et al. 1984, 1987). Some metal ions may be excluded from bacterial cells. In that case, no toxicity is seen, even at very high concentrations (Rossman et al. 1984). Essential bacterial enzymes may be more sensitive than their mammalian counterparts to metal ion inhibition, resulting in toxicity which masks the mutagenicity. In some 

Metal Induction of SOS response Ames test Modified Ames test  

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Klein, C.B. Rossman. T.G. (1990) Transgenic Chinese hamster V79 cell lines which exhibit variable levels of gpt mutagenesis. Environ, mol. Mutag., 16, 1-12... 

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. 

Rossman, T.G. (2003) Mechanism of arsenic carcinogenesis an integrated approach. Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis, 533(1-2), 37-65. 

Roy NK and Rossman TG (1992) Mutagenesis and comutagenesis of lead compounds. Mutat Res 298 97-103. 

Chinese hamster G-12-V79 cells with one copy gpt gene Ham s FI 2 + 5% FBS DNA strand breaks defined as nick translation Pb (acetate) 1,700 pM, 5 days mutagenesis-gpt Pb (nitrate) 5—2,000 pM, 5 days Pb did not induce single-strand breaks Pb not mutagenic Roy and Rossman (1992)... 

Studies on mutagenesis by metal compounds may be complicated by inducible tolerance mechanisms in some cells. Metallothioneins (MT) are small cysteine-rich proteins which bind a number of metals with high affinity. The reader is referred to Chap. 5 in this volume for more detail. Besides cadmium, zinc, and copper salts, a number of other metal salts have also been shown to induce MT synthesis and/or to bind to the MT protein. Hg(II), Co(II), and Ni(II), but not Pb(II), induce MT synthesis in primary cultures of rat hepatocytes (Bracken and Klaassen 1987), and may do so in the cultured cells used for mammalian mutagenesis experiments. Thus, under some experimental protocols, the metal salt being assayed may itself induce metallothionein, or the results of mutagenicity assays may be confounded by components of the medium or serum which affect the levels of metallothionein in the cell (Rossman and Goncharova, unpublished). 

Substitution of Mn(II) for Mg(II) in DNA polymerases results in decreased fidelity (Goodman et al. 1983 Beckman et al. 1985). Under conditions where Mn(II) is not mutagenic, it enhanced UV-induced mutagenesis in E. coli (Rossman and Molina 1986). A likely explanation for the comutagenic effect is that Mn(II) affects DNA replication of a damaged template. This was shown in the case of alkylation damage, where Mn(II) facilitated postlesion synthesis which was accompanied by misincorporation opposite the alkylated bases (Bhanot and Solomon 1994). 

Goncharova El, Rossman TG (1994) A role for metallothionein and zinc in spontaneous mutagenesis. Cancer Res (in press)... 

Lee YW, Pons C, Tummolo DM, Klein CB, Rossman TG, Christie NT (1993) Mutagenicity of soluble and insoluble nickel compounds at the gpt locus in G12 Chinese hamster cells. Environ Mol Mutagen 21 365-371 Lee-Chen SF, Yu CT, Jan KY (1992) Effect of arsenite on the DNA repair of UV-irradiated Chinese hamster ovary cells. Mutagenesis 7 51-55 Leonard A (1984) Recent advances in arsenic mutagenesis and carcinogenesis. Toxicol Environ Chem 7 241-250... 

Rossman TG (1981) Enhancement of UV-mutagenesis by low concentrations of arsenite in E. coli. Mutat Res 91 207-211... 

Rossman TG (1989) On the mechanism of the comutagenic effect of Cu(II) with ultraviolet light. Biol Trace Elem Res 21 383-388 Rossman TG, Molina M (1986) The genetic toxicology of metal compounds. II. Enhancement of ultraviolet light-induced mutagenesis in E. coli WP2. Environ Mutagen 8 263-271... 

Rossman TG, Molina M, Meyer L, Boon P, Klein CB, Wang Z, Li F, Lin WC, Kinney PL (1991) Performance of 133 compounds in the lambda induction endpoint of the Microscreen assay and a comparison with Salmonella mutagenicity and rodent carcinogenicity bioassays. Mutat Res 260 349-367 Roy NK, Rossman TG (1992) Mutagenesis and comutagenesis by lead compounds. Mutat Res 298 97-103... 

M. S. Meyn, T. Rossman, and W. Troll, A protease inhibitor blocks SOS functions in Escherichia colt Antipain prevents X repressor inactivation, ultraviolet mutagenesis, and filamentous growth, Proc. Natl. Acad. Sci. U S A. 74, 1152-1156 (1977). 

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