The ratio of induced recessive lethals to ring-X loss has prognostic value in terms of functionality of chemical mutagens in Drosophila melanogaster.
For 25 mutagens in Drosophila the ratio was determined between the induction of sex-linked recessive lethals (SLRL) and the induction of ring-X loss in male adults. For small monofunctional alkylating agents this ratio increases with decreasing s-value from 1.8 for methyl methanesulfonate (MMS) to 27 for ethylnitrosourea (ENU). For multifunctional cross-linking agents, however, the ratio varies within relatively narrow limits, ranging from 0.15 for cisplatin to 0.07 for tris-(1-aziridinyl)phosphineoxide (TEPA), while for most agents the ratio is around 0.12. The number of reactive groups seems to be of minor importance for compounds with more than one functionality as bi- and tri-functional agents show similar ratios. The systemic difference in the ratios between mono- and multi-functional agents suggests that different mechanisms are involved in the induction of SLRLs and ring-X loss. For ethyleneimine (EI) and ethyleneoxide (EO) low ratios of 0.32 and 0.60 respectively were observed which do not correlate with their s-values. An alternative chromosome-breaking mechanism may be responsible for this deviation, possibly alkylation of the phosphate backbone of DNA, followed by an intramolecular displacement of one of the deoxyribose groups by the beta-amino or the beta-hydroxy group. It is felt that the considerable difference between the ratios for monofunctional and multifunctional agents may be of prognostic value and can be used to obtain information on the mechanisms of mutagens with 'unknown' action, provided that structural features are taken into account. Hexamethylphosphoramide (HMPA), hexamethylmelamine (HEMEL), tetramethylurea (TMU) and dimethylpropyleneurea (DMPU) all show SLRL: ring-X loss ratios that match those of multifunctional agents, 0.08, 0.12, 0.08, and 0.16, respectively. The ratios for the pyrrolizidine alkaloids monocrotalin and seniciphilline, 0.053 and 0.24 respectively, also correspond with this group of mutagens. The low ratios for formaldehyde, 2-chloro-acetaldehyde and 2-chloroethyl methanesulfonate, 0.30, 0.052 and 0.36 respectively, are indicative that cross-linking may attribute considerably to their mutagenic action in Drosophila. On the other hand, not all mutagens containing 2 reactive groups act as cross-linking agents. The ratio for 1,2-dibromoethane, 2.7, indicates that it may act as a monofunctional agent. This is in accordance with the proposed activation mechanism by glutathione S-transferase, producing a monofunctional half-mustard derivative (Rannug, 1980; van Bladeren et al., 1981).
Zijlstra
J A
JA
Department of Radiation Research and Chemical Mutagenesis, University of Leiden, The Netherlands.
Vogel
E W
EW
D000477:Alkylating Agents / Q000494:pharmacology; D000818:Animals; D002869:Chromosome Aberrations / Q000187:drug effects*; D002945:Cisplatin / Q000494:pharmacology; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004249:DNA Damage; D004331:Drosophila melanogaster / Q000235:genetics*; D005038:Ethylnitrosourea / Q000494:pharmacology; D005804:Genes, Lethal / Q000187:drug effects*; D008297:Male; D008741:Methyl Methanesulfonate / Q000494:pharmacology; D009152:Mutagenicity Tests; D009153:Mutagens / Q000494:pharmacology*; D012303:Ring Chromosomes; D013721:Triethylenephosphoramide / Q000494:pharmacology
D000477:Alkylating Agents; D003432:Cross-Linking Reagents; D009153:Mutagens; D008741:Methyl Methanesulfonate; D013721:Triethylenephosphoramide; D005038:Ethylnitrosourea; D002945:Cisplatin