High recombinagenic activities of three antiviral agents, adenine derivatives, in the Drosophila wing spot test.

Three adenine derivatives, (R,S)-9-(2,3-dihydroxypropyl)adenine (DHPA), D-eritadenine (EA), and 9-(2-phosphonylmethoxyethyl)adenine (PMEA), prospective antiviral drugs, were subjected to genotoxicity analysis using the somatic mutation and recombination test in Drosophila melanogaster. All three compounds were found to be very potent inducers of mosaic spots on Drosophila wings in a dose-related fashion. Data obtained in inversion-free flies revealed that the compounds, in particular DHPA and EA (nucleoside analogues), are highly effective in the induction of mitotic recombination. PMEA, a nucleotide analogue, exhibited a rather different genotoxic profile from those of DHPA and EA, indicating a different mechanism of genetic action of this compound. Of somatic mutations, chromosome aberrations rather than point mutations seem to play a major role in the genotoxicity of PMEA. In flies carrying an inversion chromosome, which eliminates most products of mitotic recombination, reduced spot frequencies were obtained, which, however, were still unexpectedly high for compounds with strong recombinagenic activities. Most probably, in addition to structural mutations of chromosome, double mitotic crossing-over and non-reciprocal recombination events similar to unequal sister-strand recombination or gene conversion significantly contributed to spot induction in the inversion heterozygous flies. Concerning the mechanism of genotoxic action, we suggest that these adenine derivatives can be incorporated into DNA chains during replication. This would result, via breaks and DNA repair mechanisms, either in various recombination events or in chromosome aberrations.