For many DNA-damaging agents, the extent of damage at any given base site is influenced by the DNA sequence surrounding that site. Most agents that alkylate the guanine N7 position, including mechlorethamine (nitrogen mustard) and benzo[a]pyrene diol epoxide, alkylate oligo-guanine sequences preferentially. Since these data suggest that guanine-cytosine(GC)-rich regions in genes could be preferred sites of damage by these agents, GenBank was searched for genes containing 30 bp sequences of greater than 90% GC (GC runs). While primate, rodent, other mammalian, vertebrate and animal virus genes constituted 57% of the annotated entries, they included 90% of the entries with the GC runs. In addition, the percentage of oncogenes in the group of the entries with GC runs was higher than that in the overall database. One gene of interest containing GC runs was the human c-Ha-ras oncogene. All seven GC runs in the c-Ha-ras gene are in the 5'-flanking region, rather than in the coding sequences. In fact, some of the GC runs are contained in Sp1-binding enhancer sequences. Gel analysis of the alkylation of cloned c-Ha-ras DNA by several carcinogenic alkylating agents strongly suggest that in this gene GC runs can be preferred sites of damage. These observations suggest mechanisms by which DNA damage at sites other than oncogene coding sequences may play a role in carcinogenesis and/or chemotherapy.
A series of 12 organosilicon compounds representing potential intermediates in the synthesis and degradation of polydimethylsiloxanes were evaluated for genotoxic potential with a battery of in vitro assays. Microbial assays included the Ames bacterial reverse mutation in Salmonella, mitotic gene conversion in Saccharomyces cerevisiae D4 and DNA repair in E. Coli pol A +/-. These assays were conducted with and without a metabolic activation system containing Aroclor 1254-induced rat-liver homogenate. Forward gene mutation, sister-chromatid exchange, DNA alkaline elution and chromosome aberration potential were evaluated in mouse lymphoma L5178Y tissue culture cells. The tissue culture assays were performed with and without metabolic activation mixture utilizing uninduced mouse-liver S-9. The use of this enzyme preparation was felt to more closely mimic the actual in vivo situation and to be more compatible with mouse cells employed in the assay. No evidence of gene mutation was observed. However, six of the 12 compounds evaluated demonstrated potential in vitro clastogenic (chromosome damaging) activity.
Erythrocytes from patients with congenital muscular dystrophy exhibit dramatic surface deformation when observed with a scanning electron microscope. A similar alteration, but one affecting a smaller proportion of cells, occurs in the case of female carriers of the sex-linked Duchenne dystrophic condition. These observed changes in the erythrocyte surface may reflect a systemic defect in membrane properties.
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