The genetic toxicology of 2-amino-N6-hydroxyadenine in eukaryotic organisms: significance for genetic risk assessment.
A collaborative study was designed to assess the mutagenicity of 2-amino-N6-hydroxylaminopurine (AHA) in a wide variety of eukaryotic assays systems in terms of potency and specificity. Earlier studies in Salmonella and Neurospora had shown that AHA was an extremely potent mutagen which appeared to cause predominantly AT to GC base-pair transitions. This discovery was viewed as an unusual opportunity to explore the general utility of different eukaryotic assay systems for genetic risk assessment. The objective was to determine whether AHA would show comparable potency and specificity in those eukaryotic organisms used to evaluate mutagenic potential of environmental chemicals for the human population. The data presented in this report show that AHA was mutagenic in all the eukaryotic assays utilized; however, the level of effect was found to be assay system-dependent. In addition, in assays where other base analogs were used as positive controls, differences in relative potency were observed from those obtained in the earlier studies with Salmonella and Neurospora. When alkylating agents were used as positive controls in the higher eukaryotic assays, AHA was found to have a mutagenic potency comparable to ethylnitrosourea (ENU), ethyl methanesulfonate (EMS) or methyl methanesulfonate (MMS) for many of the assays. With regard to mutagenic specificity, AHA appears to induce gene/point mutations in eukaryotic organisms, resulting predominantly from base-pair substitutions, predominantly AT to GC base-pair transitions; however, there was some unexplained variation in the ratio of these base-pair transitions and other transitions and transversions as a function of assay system. In addition, studies on the induction of micronuclei have shown that AHA induces chromosomal damage at high concentrations and low levels of survival.
de Serres
F J
FJ
Center for Life Sciences and Toxicology, Research Triangle Institute, Research Triangle Park, NC 27709.
D000225:Adenine / Q000031:analogs & derivatives* / Q000633:toxicity; D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D004330:Drosophila; D005057:Eukaryotic Cells / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D009152:Mutagenicity Tests / Q000592:standards*; D009153:Mutagens
D009153:Mutagens; C030632:2-amino-N(6)-hydroxyadenine; D000225:Adenine