The mutagenicity of 2-amino-N6-hydroxyadenine to L5178Y tk +/- 3.7.2C mouse lymphoma cells: measurement of mutations to ouabain, 6-thioguanine and trifluorothymidine resistance, and the induction of micronuclei.
2-Amino-N6-hydroxyadenine (AHA) was tested in the mouse lymphoma L5178Y tk +/- assay using the microtitre cloning technique over concentrations from 0.005 micrograms/ml-1 (100% viability) to 6 micrograms/ml (10% viability) as measured by cloning efficiency immediately after treatment. At low, non-toxic concentrations (0.005-0.25 micrograms/ml) a dose-related linear increase in the frequency of ouabain-resistant mutants was seen, in addition to an increase in 6-thioguanine- and trifluorothymidine-resistant mutants. No consistent induction of micronucleated cells was observed in this concentration range. Toxic concentrations (20-90% kill) induced a dose-related increase in micronuclei, while the frequency of ouabain-resistant mutants fell (although it was still highly significantly above the control value). These results suggest that the mechanism of action of AHA depends on the concentration, with point mutations being induced at low, non-toxic doses and detectable chromosome breakage occurring only at higher doses. Both large-colony and small-colony trifluorothymidine-resistant mutants were induced at all concentrations. The utility of using multiple genetic end-points in one cell line and the importance of dose range selection for risk assessment and an understanding of the mode of action of test substances is underlined.
Cole
J
J
MRC Cell Mutation Unit, University of Sussex, Falmer, Brighton, Great Britain.
Richmond
F N
FN
Bridges
B A
BA
D000225:Adenine / Q000031:analogs & derivatives* / Q000633:toxicity; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D008223:Lymphoma; D051379:Mice; D015162:Micronucleus Tests; D009152:Mutagenicity Tests; D009153:Mutagens; D010042:Ouabain / Q000494:pharmacology; D013866:Thioguanine / Q000633:toxicity; D013937:Thymidine Kinase / Q000235:genetics; D014271:Trifluridine / Q000633:toxicity; D014407:Tumor Cells, Cultured
D009153:Mutagens; D010042:Ouabain; C030632:2-amino-N(6)-hydroxyadenine; D013937:Thymidine Kinase; D013866:Thioguanine; D000225:Adenine; D014271:Trifluridine