ABSTRACT
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.
Subject(s)
Antidepressive Agents, Tricyclic/toxicity , Mutagens/toxicity , Animals , Antidepressive Agents, Tricyclic/chemistry , CHO Cells , Chlorpromazine/toxicity , Clomipramine/toxicity , Cricetinae , Drosophila melanogaster , Female , Lofepramine/toxicity , Male , Maprotiline/toxicity , Mianserin/toxicity , Mutagenicity Tests , Recombination, Genetic , Structure-Activity RelationshipABSTRACT
Data presented show that lofepramine has lower acute toxicity for animals than other antidepressants tested. Review of 55 case reports of acute lofepramine overdose in man shows that hypotension was rare and convulsions did not occur, although in some cases large overdoses of several grams of drug had been taken. No deaths have been recorded due to overdose with lofepramine alone, and the fatal toxicity index for lofepramine (deaths per million prescriptions, England, Wales and Scotland, 1982-1986) is significantly lower than the mean of all antidepressants (P less than 0.001). It thus appears that the low toxicity of lofepramine in animal experiments applies also to man, and that this drug has a favourable safety profile when taken in acute overdose.
