Genetic method for pre-classification of genotoxins into monofunctional or cross-linking agents.
To characterize environmental carcinogens, there is a need to distinguish monofunctional genotoxic agents from those having cross-linking potential, because chemicals which can cross-link DNA are among the most potent carcinogens in rodents [Barbin and Bartsch, 1989] and humans [Allen et al., 1988; Kaldor et al., 1988]. Here we provide a genetic method for a pre-classification of genotoxins with respect to their functionality--monofunctional versus cross-linking. The procedure is based on the determination of relative clastogenic efficiency by a two-endpoint comparison in Drosophila: (i) induction of chromosome loss (CL), (ii) incidence of recessive lethal mutations (RL). Analysis of CL/RL ratios of 53 genotoxins, all mutagens in Drosophila, permitted distinction of 45 into two major categories: (i) 21 monofunctional agents with CL/RL indices generally < or = 1; (ii) 24 agents with ratios > 2 exhibiting DNA cross-linking properties. Within the group of monofunctional agents, CL/RL ratios tend to be low for SN1 agents, i.e., for N-ethyl-N-nitrosourea, N-ethyl-N'-nitro-N-nitrosoguanidine, and for N-nitrosodiethylamine. With cross-linking agents, the number of reactive groups appeared of minor importance as bi-, tri-, and tetrafunctional agents showed no significant differences in their CL/RL indices. Among 8 chemicals which could not be grouped into one of the two categories are two (adriamycin, daunomycin) regarded as intercalating agents. It is concluded that this two-endpoint analysis in Drosophila has prognostic value and can assist in the characterization of genotoxic agents with unknown mode of action.
Vogel
E W
EW
MGC, Department of Radiation Genetics & Chemical Mutagenesis, University of Leiden, The Netherlands.
Zijlstra
J A
JA
Nivard
M J
MJ
D000477:Alkylating Agents / Q000633:toxicity; D000818:Animals; D002872:Chromosome Deletion; D003432:Cross-Linking Reagents / Q000633:toxicity*; D004247:DNA / Q000187:drug effects; D004330:Drosophila / Q000187:drug effects* / Q000235:genetics; D005260:Female; D005804:Genes, Lethal; D005808:Genes, Recessive; D007364:Intercalating Agents / Q000633:toxicity; D008297:Male; D008745:Methylation; D016296:Mutagenesis; D009152:Mutagenicity Tests / Q000379:methods*; D009153:Mutagens / Q000737:chemistry / Q000145:classification* / Q000633:toxicity; D009154:Mutation; D015203:Reproducibility of Results
D000477:Alkylating Agents; D003432:Cross-Linking Reagents; D007364:Intercalating Agents; D009153:Mutagens; D004247:DNA