Nucleophilic selectivity of alkylating agents and their hypermutability in Drosophila as predictors of carcinognic potency in rodents

Abstract

The nucleophilic selectivity (Swain-Scott s constant or initial 7-alkylguanine/O6-alkylguanine ratio in DNA) of 60 alkylating agents, mostly monofunctional or cross-linking was compared to their carcinogenic potency in rodents (median TD50 estimates) and to two genotoxicity indices in Drosophila: (i) hypermutability, measured by the increased frequency of induced sex-linked recessive lethal mutations (SLRL) in a strain defective in DNA excision repair (exr-), as compared to the wild-type (exr+); (ii) relative clastogenic efficiency, expressed by the ratio of chromosomal aberrations (ring-X loss) to SLRL determined in the exr+ strain. For a subset of direct-acting, monofunctional alkylating agents, nucleophilic selectivity and TD50 values or hypermutability indices were linearly correlated. In addition, the hypermutability indices in Drosophila by methylating or ethylating procarcinogens were similar to the corresponding values of their ultimate metabolites. In contrast, cross-linking agents, including antitumour drugs, did not show these positive correlations. The relative clastogenic efficiencies in Drosophila of 26 direct-acting, alkylating carcinogens increased with both their cross-linking activity and nucleophilic selectivity. By analyzing mutational spectra in Drosophila induced in the vermilion gene by four monofunctional alkylating agents with contrasting s values, critical DNA lesions, i.e. type of base pair substitution mutations, deletions, insertions, involved in genotoxicity were pinpointed. Thus, these multi-endpoint analyses should, as a new approach, assist in the quantitative risk evaluation of genotoxic agents.

In vivo repair of ENU-induced oxygen alkylation damage by the nucleotide excision repair mechanism in Drosophila melanogaster

“…This is supported by previous studies with MNU (Nivard et al 1996) and DES , in which the frequency of base pair substitutions induced by O-alkylation increased in ner ± respect to ner + conditions. O-alkylation of DNA is the most signi®cant type of ENU-induced damage, from the point of view of its mutagenic eect, and it has been directly correlated with the mutagenic and carcinogenic potency of alkylating agents (Newbold et al 1980;Bartsch et al 1983;van Zeeland et al 1985;Vogel et al 1990). In spite of this, the cellular mechanisms involved in the response to Oalkylations, especially the repair systems involved, have remained uncertain in higher eukaryotic organisms.…”

“…Oxygen alkylation, although it occurs less frequently than N-alkylation (Beranek 1990), positively correlates with the induction of point mutations (Vogel and Nivard 1994), and has been correlated with the mutagenic and carcinogenic potency of alkylating agents (Newbold et al 1980;Bartsch et al 1983;van Zeeland et al 1985;Vogel et al 1990). Among the oxygen atoms in the DNA bases, O 6 -guanine is the most frequently alkylated position, followed by O 2 -thymine, O 4 -thymine, and O 2 -cytosine (Beranek 1990).…”

Genotoxicity and anti-genotoxicity of fennel plant (Foeniculum vulgare Mill) fruit extracts using the somatic mutation and recombination test (SMART)

“…The mutational spectra induced in Drosophila by MMS suggest the involvement of apurinic sites as mutagenic lesions (Vogel et al, 1990). In addition, a clear relationship exists between the extent of the DNA Nalkylation and the efficiency of the MMS to induce mitotic recombination in the Drosophila wing-spot test (Arnaiz et al, 1996).…”

Study on antigenotoxic effects of Moroccan medicinal plants and spices using the <i> white/white</i> + somatic assay in <i> Drosophila</i>

“…The mutagenicity and carcinogenicity of monofunctional alkylating agents, including MMS, have been associated with the formation of O-alkylated and N-alkylated DNA bases (Vogel and Nivard, 1994). The mutational spectra induced in Drosophila by MMS suggest the involvement of apurinic sites as mutagenic lesions (Vogel et al, 1990). In addition, a clear relationship exists between the extent of the DNA N-alkylation and the efficiency of the MMS to induce mitotic recombination in the Drosophila wing-spot test (Rodriquez-Arnaiz et al, 1996).…”