Base pair substitution

The mutagenicity of benzofa]pyrene for bacteria was demonstrated by Ames et al. (60) They found that in the presence of rat liver homogenates benzo[a]pyrene induced both frameshift and base-pair substitution mutations. When the chemistry of benzo[a]pyrene activation had been worked out and the ultimate carcinogenic form identified as a diolepoxide, BPDE (reviewed in 61-62), several investigators (63-66) showed that BPDE was an extremely potent mutagen, also capable of inducing both frameshift and base-pair substitution mutations. 

We have not directly determined the relative frequencies of frameshift mutations and other mutational events in comparison to the base substitution mutations. However, based on the high frequency of nonsense mutations (11%) among all lacl mutants induced by BPDE and because nonsense mutations are monitorable at less than one-fifth of the lacl codons and, even then, only via certain base pair substitutions, we believe that base substitutions account for a major fraction of mutations induced by BPDE. 

TA1535 hisG46 rfa / gal chlD bio uvrB Subset of base-pair substitution events... 

Bridges, B.A., Woodgate, R., Ruiz-Rubio, M., Sharif, F., Sedgwick, S.G. and Huhschere, U. (1987). Current understanding ofUV-induced base pair substitution mutation inE. coli with particular reference to the DNA polymerase III complex. Mutation Res. 181 219-226. 

In bacterial systems, 1,2-dibromoethane is a direct-acting mutagen and primarily causes mutations of the base-pair substitution type (Barber et al. 1981 McCann et al. 1975 Moriya et al. 1983 ... 

Positive results from the Saccharomyces cerevisiae gene mutation assay indicate that a substance induces point mutations by base pair substitution or frameshift in the genome. Base pair substimtion and frameshift is explained under the in vivo test. 

Figure 3. Mutagenic activities of the promutagens cis- and Xrms-diallate and sulfallate, the proximate mutagen cis-diallate sulfoxide, and the ultimate mutagen 2-chloroacrolein, assayed with S. typhimurium strain TA 100 sensitive to base-pair substitution mutagens. The diallate isomers and sulfallate are not mutagenic without the S9 mix. S9 mix refers to a microsomal oxidase system prepared from rat liver and appropriate cofactors. The methodology is detailed in Refs. 6, 22, and 29.

This assay employs a number of different strains of Salmonella typhimurium mutants that are histidine auxotrophs. The first tester strains developed and tested on extracts of diesel and ambient POM in the mid to late 1970s included TA1535, which responds to base-pair substitution chemical mutagens (e.g., /f -propiolac-tone), and TA1537 and TA1538, which respond to frameshift mutagens, e.g., BaP and other PAHs. 

Fischer SG, Lerman LS (1983) DNA fragments differing by single base-pair substitutions are separated in denaturing gels correspondence with melting theory. Proc Natl Acad Sci USA 80 1579-1584... 

DNA base sequence changes were analysed in 31 transmissible vermilion mutants recovered from Drosophila melanogaster, the male germ cells of which had been treated with diethyl sulfate. There were 93% base-pair substitutions and 7% deletions. The most frequent base-pair changes were GC—>AT transitions (73%) and AT—>TA transversions (10%) (Sierra et al., 1993). 

DNA isolated from cells (Kessel et al., 2002) and tissues and urine of animals (Vijayaraghavan et al., 2001 Yamanaka et al., 2001) treated with arsenic show lesions induced by oxidative stress. These lesions include 8-oxo-2 -deoxyguanosine and 8-hydroxy-2 -deoxyguanosine. These DNA lesions may lead to base-pair substitutions (guanine to thymidine and adenine to cytosine) during DNA synthesis, which could lead to altered gene products. 

The positive dose-response results of the mutagen assays are of interest since both strains showed the nitrosated product to be direct-acting mutagens for both TA98 and TA100 strains. Most N-nitroso compounds cause mutations by base-pair substitution only... 

Our early findings48,97) that cisplatin induces base-pair substitutions in -GCG- and -GAG- base sequences in bacterial DNA (E. coli) and thus plays a role in the mutagenic... 

The question which of the induced Pt-DNA adducts is (are) responsible for the antitumor activity is still unanswered. Many investigators have tried to correlate interstrand DNA and DNA-protein crosslink formation with the cytotoxic action of cisplatin. However, conflicting results were obtained18,50 Until now a biological role inside the cell has been indicated for only one type of Pt-DNA adduct. Brouwer et al.48 showed that cisplatin can induce base-pair substitutions in E. coli bacteria at GAG and GCG base sequences. This strongly suggests that the intrastrand crosslink of cisplatin on GBG is responsible for this effect. 

As shown in Tables 2-7 and 2-8, there are both in vitro and in vivo genotoxicity data for organotin compounds, particularly bis(tributyltin)oxide. The results from most in vitro studies were negative. However, base-pair substitutions were produced in an activated Salmonella typhimurium fluctuation test of bis(tributyltin)oxide (Davis et al. 1987). In addition, bis(tributyltin)oxide produced chromosomal aberrations in hamster ovary cells with activation (Davis et al. 1987). In vivo micronucleus tests of bis(tributyltin)oxide in mice produced mixed results (Table 2-8). The relevance of the genotoxic data to humans is not clear. 

The di-, tri-, and sulfallates were classified as potent mutagens in the Ames assay with TA 100 and TA 1538 (base-pair substitution mutants), with metabolic activation required (1978). More recent in vitro testing (1981) of di- and triallate with S. typhimurium (strains TA1535.-100, and -98) showed dose-related increases without metabolic activation, but greatly enhanced mutagenicities in the presence of Aroclor 1254-induced rat liver S-9 fraction. These tests indicated that both the di- and triallates can induce base pair substitution and frame shift mutations. 

The two possible consequences of base-pair substitution are that the gene encodes for either no amino acid or the wrong amino acid. Effects can range from minor results to termination of protein synthesis. 

Several researchers used the Ames test with Salmonella typhimurium to assess the mutagenicity of 2,3,7,8-TCDD in prokaryotic organisms. Predominantly negative results were obtained with tester strains G46, TA 1530, TA 1535, TA 100, TA 1950, and TA 1975, revealing base pair substitutions and with strains TA 1531, TA 1532, TA 1534, TA 1538, TA 98, and TA 1978, revealing frame shift mutations (Geiger and Neal 1981 Gilbert et al. 1980 Mortelmans et al. 1984 Toth et al. 1984). 

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