Nucleophilic selectivity of alkylating agents and their hypermutability in Drosophila as predictors of carcinogenic potency in rodents.
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.
Vogel
E W
EW
Department of Radiation Genetics and Chemical Mutagenesis, Sylvius Laboratories, Leiden, The Netherlands.
Barbin
A
A
Nivard
M J
MJ
Bartsch
H
H
D000477:Alkylating Agents / Q000737:chemistry*; D000478:Alkylation; D000818:Animals; D015197:Carcinogenicity Tests; D003432:Cross-Linking Reagents; D004260:DNA Repair / Q000187:drug effects; D004330:Drosophila / Q000235:genetics; D009152:Mutagenicity Tests; D009154:Mutation; D012377:Rodentia
D000477:Alkylating Agents; D003432:Cross-Linking Reagents