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© 1990 Oxford University Press

other

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

Ekkehart W. Vogel, Alain Barbin 1, Madeleine J.M. Nivard and Helmut Bartsch 1

Department of Radiation Genetics and Chemical Mutagenesis, Sylvius Laboratories Leiden, The Netherlands
1International Agency for Research on Cancer Lyon, France

The nucleophilic selectivity (Swain-Scott s constant or initial 7-alkylguanine/O6 -alkylguanine ratio in DNA) of 60 alkylating agents, mostly monofunctlonal 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 hyper mutability 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.


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