Structure-activity relationships of tricyclic antidepressants and related compounds in the wing somatic mutation and recombination test of Drosophila melanogaster.
Four antidepressants and one neuroleptic drug were tested for genotoxicity using the somatic mutation and recombination test (SMART) in wing cells of Drosophila melanogaster. Three-day-old larvae trans-heterozygous for two linked recessive wing hair mutations (multiple wing hairs and flare) were fed the test compounds in water or solvents mixed with a standard dry food for 48 h. Wings of the emerging adult flies were scored for the presence of spots of mutant cells which can result from either somatic mutation or mitotic recombination. The tricyclic antidepressant clomipramine, which is closely related to imipramine (previously shown to be genotoxic in somatic cells of Drosophila), was clearly genotoxic at concentrations above 10 mM. The structurally related antidepressants lofepramine and mianserin were positive only at 100 mM which is the maximum tolerated dose. The antidepressant maprotiline and the antipsychotic chlorpromazine, which are distinguished from the other compounds by a 6-membered central ring instead of a 7-membered one, were not genotoxic in the same dose range. These results lend further support for the hypothesis that an N atom in the heterocyclic 7-membered ring of the tricyclic molecule is responsible for the genotoxic property of the compounds in Drosophila.
van Schaik
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N
Institute of Toxicology, Swiss Federal Institute of Technology, Schwerzenbach.
Graf
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U
D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000737:chemistry / Q000633:toxicity*; D016466:CHO Cells; D002746:Chlorpromazine / Q000633:toxicity; D002997:Clomipramine / Q000633:toxicity; D006224:Cricetinae; D004331:Drosophila melanogaster; D005260:Female; D008127:Lofepramine / Q000633:toxicity; D008297:Male; D008376:Maprotiline / Q000633:toxicity; D008803:Mianserin / Q000633:toxicity; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity*; D011995:Recombination, Genetic; D013329:Structure-Activity Relationship
D000929:Antidepressive Agents, Tricyclic; D009153:Mutagens; D008803:Mianserin; D008376:Maprotiline; D002997:Clomipramine; D008127:Lofepramine; D002746:Chlorpromazine