Metabolic inactivation of mutagens in Drosophila melanogaster.
The route of administration of a drug is a pharmacological factor to be reckoned with. In Drosophila, a whole-animal object for mutagenicity studies, the way in which a mutagen is applied can also be of crucial importance. In this study the mutagenicity of a number of directly acting agents was determined after feeding or injection of the mutagen. Methyl-p-toluenesulphonate (Me-Tos), ethyl-p-toluenesulphonate (Et-Tos) and nor-nitrogen mustard (NNM) were not mutagenic in a sex-linked recessive lethal test when fed to the adult flies. Injection, however, did produce significant mutagenicity. The absence of mutagenicity after oral application is not caused by chemical instability but is the result of metabolic de-activation, presumably in the gut and the fat body. Feeding of these compounds in combination with the inhibition of cytochrome P-450 by 1-phenylimidazole (PhI) allowed sufficient quantities of the mutagen to reach the gonads and to produce significant genetic damage. This resembles what is known in pharmacology as a 'first-pass effect'. Formaldehyde (FA) mutagenicity, which also is only observed after injection and not in feeding experiments, was not affected by either iproniazid (Ipr) or PhI pretreatment. Aspecific enhancement of mutagenicity is excluded as this effect was not observed with mutagens that are structurally related to the tosylates, such as methyl methanesulphonate (MMS), ethyl methanesulphonate (EMS) or hycanthone methanesulphonate (HyMS). A number of other inhibitors of metabolism did not influence metabolic de-activation in Drosophila.
D000818:Animals; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism*; D005502:Food; D005804:Genes, Lethal / Q000187:drug effects; D005808:Genes, Recessive / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology; D008658:Inactivation, Metabolic; D007267:Injections; D007814:Larva; D009152:Mutagenicity Tests / Q000379:methods; D009153:Mutagens / Q000008:administration & dosage / Q000378:metabolism*; D014018:Tissue Distribution
D065607:Cytochrome P-450 Enzyme Inhibitors; D007093:Imidazoles; D009153:Mutagens; C037738:1-phenylimidazole; D003577:Cytochrome P-450 Enzyme System