Comparison of dose-response relationships for ethyl methanesulfonate and 1-ethyl-1-nitrosourea in Drosophila melanogaster spermatozoa.
The relative importance of different sites of alkylation on DNA was determined by comparing two ethylating agents. 1-Ethyl-1-nitrosourea (ENU) ethylates DNA with a higher proportion of total adducts on ring oxygens than ethyl methanesulfonate, which ethylates with a higher proportion of total adducts on the N-7 of guanine. Research with somatic cells in culture and prokaryotes strongly suggests that O6-guanine (O6-G) is the principal genotoxic site. To determine the importance in germ-line mutagenesis of the O6-G site relative to the N-7 of guanine, dose-response curves were constructed for both ENU and EMS, where dose was measured as total adducts per deoxynucleotide (APdN) and response as sex-linked recessive lethals (SLRL) induced in Drosophila melanogaster spermatozoa. For both mutagens the dose response curve was linear and extrapolated to the origin. The dose-response curve for ENU was fit to an equation m = 6.2D, and the dose response curve for EMS, from this and previous experiments, was m = 3.2D where m = %SLRL and D = APdN X 10(-3). Therefore, ENU is 1.9 times more efficient per adduct in inducing SLRL mutations than EMS. In vitro studies showed that ENU induced 9.5% of its total adducts on O6-G while EMS induced 2.0% of its adducts on O6-G. If O6-G was the sole genotoxic site, then ENU should be 4.8 times more efficient per adduct than EMS. In contrast, if N-7 G was the sole genotoxic site, ENU would be only 0.19 as effective as EMS. It was concluded that while O6-G was the principal genotoxic site, N-7 G made a significant contribution to germ-line mutagenesis.
Lee
W R
WR
Department of Zoology and Physiology, Louisiana State University, Baton Rouge.
Beranek
D T
DT
Byrne
B J
BJ
Tucker
A B
AB
D000818:Animals; D002250:Carbon Radioisotopes; D003433:Crosses, Genetic; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004331:Drosophila melanogaster / Q000187:drug effects / Q000235:genetics*; D005020:Ethyl Methanesulfonate / Q000378:metabolism / Q000494:pharmacology*; D005038:Ethylnitrosourea / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D008297:Male; D009152:Mutagenicity Tests / Q000379:methods; D009154:Mutation; D011865:Radioisotope Dilution Technique; D013094:Spermatozoa / Q000187:drug effects*; D013936:Thymidine / Q000378:metabolism; D014316:Tritium
D002250:Carbon Radioisotopes; D014316:Tritium; D004247:DNA; D005020:Ethyl Methanesulfonate; D005038:Ethylnitrosourea; D013936:Thymidine