The principle objective of this research project is to utilize the fruitfly Drosophila melanogaster as a model system for investigating some fundamental genetical and biochemical aspects in chemical mutagenesis. Major emphasis will be placed on basic relationships between the structure of a chemical mutagen, its initial mode of interaction with DNA, the modifying (e.g. repair) factors affecting the expression of genetic damage and, as far as possible, all of its genotoxic properties. To achieve this goal, it is proposed to conduct analysis of multiple (eight) genetic endpoints in combination with DNA-binding studies. The model mutagens selected are some mythylating and ethylating agents, hexamethylphosphoramide and 7,12-DMBA. The genetic part of the work will further include (i) the validation of somatic mutation tests as fast diagnostic tools for prescreening of environmental mutagens and (ii) a comparison of the resolving power of specific-locus tests relative to multi-locus procedures. The latter project deserves particular attention because in mammals the specific locus test in mice is currently used in the quantitative evaluation of hazards resulting from exposure of environmetal mutagens. On the biochemical side, it is intended to continue the characterization of xebiotic-metabolizing enzymes involved in metabolism of procarcinogens. Here, main emphasis will be laid on (i) the analysis of enzyme inhibition in vitro (in view of the recent finding that mutagenic effectiveness of chemicals can be potentiated by inhibiting components of the drug-metabolizing enzymes); and (ii) gel electrophoresis of P-450 enzymes from different strains. It is felt that the ease, extent and facility with which biochemical aspects of chemical mutagenesis can be tackled in Drosophila, utilizing chemical methods in combination with multiple genetic parameter, is also expected to provide guidance on the kind of questions to which answers should be sought in more laborious mammalian systems.
Showing the most recent 10 out of 42 publications
