title: Influence of metabolic factors on the mutagenic effectiveness of cyclophosphamide in Drosophila melanogaster.
abstract: This paper describes the influence of changes in metabolic activity on the in-vivo mutagenic effectiveness of cyclophosphamide in Drosophila melanogaster. A dose-dependent increase in mutagenicity was observed until a plateau value is reached which was increased only slightly after enzyme induction with Aroclor 1254, whereas induction with phenobarbital resulted in a decrease, especially when cyclophosphamide was applied by injection. Treatment of the adult males with inhibitors of the monoamine oxidase (MAO, EC 1.4.3.4), such as iproniazid (Ipr), benzimidazole or tryptamine, led to a marked increase of the mutagenic effectiveness of cyclophosphamide especially in spermatocytes. This indicates the importance of metabolic de-activation processes for the limited mutagenicity of cyclophosphamide in Drosophila. The principal active metabolite of cyclophosphamide, phosphoramide mustard, is extensively de-activated by enzymes that can be inhibited by 1-phenylimidazole (PhI), presumably cytochrome P-450 (EC 1.14.14.1), but not by those blocked by MAO inhibitors. Inhibition of the FAD-containing dimethylaniline monooxygenase (FDMAM, EC 1.14.13.8) by N,N-dimethylbenzylamine (N,N-DMB) resulted in some increase in cyclophosphamide mutagenicity only in spermatids. The marginal mutagenicity of cyclophosphamide in Drosophila larvae could not be increased either by cytochrome P-450 induction with phenobarbital or by MAO inhibition with Ipr. In contrast to the failure of cyclophosphamide to induce rod-chromosome loss, a considerable activity was found when a ring-shaped chromosome was used. Similar to the sex-linked recessive lethal (SLRL) test, ring-X loss frequency could be enhanced by simultaneous treatment with MAO inhibitors. The observed ring-X loss frequency declined when males treated with cyclophosphamide were mated to DNA-repair deficient mei-9L1 females. Cyclophosphamide produces chromosome breaks, detected as 2-3 translocations, in Drosophila spermatocytes, the stage in spermatogenesis that is also the most sensitive to the induction of SLRL mutations.
authors.affiliation: Department of Radiation Genetics and Chemical Mutagenesis, University of Leiden, The Netherlands.
authors.forename: J A
authors.initials: JA
authors.lastname: Zijlstra
authors.forename: E W
authors.initials: EW
authors.lastname: Vogel
mesh_terms: D000818:Animals; D001140:Aroclors / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology; D001711:Biotransformation; D020111:Chlorodiphenyl (54% Chlorine); D003520:Cyclophosphamide / Q000378:metabolism / Q000633:toxicity*; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004331:Drosophila melanogaster / Q000235:genetics* / Q000378:metabolism; D007814:Larva; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D009154:Mutation / Q000187:drug effects*; D010634:Phenobarbital / Q000494:pharmacology; D010752:Phosphoramide Mustards / Q000633:toxicity; D014178:Translocation, Genetic
chemical_list: D001140:Aroclors; D001562:Benzimidazoles; D065607:Cytochrome P-450 Enzyme Inhibitors; D010752:Phosphoramide Mustards; C030090:phosphoramide mustard; D020111:Chlorodiphenyl (54% Chlorine); D003520:Cyclophosphamide; D003577:Cytochrome P-450 Enzyme System; C031000:benzimidazole; D006899:Mixed Function Oxygenases; D010634:Phenobarbital