Chemische Konstitution und mutagene Wirkung

Abstract

A number of bifunctional chloroethylamines with different basic structure has been tested for their mutagenic effectiveness in Drosophila. The test substances were applied orally to 1–3 day old males of the stock Berlin wild of Drosophila melanogaster and the ratios of recessive X-chromosomal lethal mutations were ascertained by means of the Base-method. In experiments to modify the mutagenic effects of phenyl-lost-derivatives by substitution in para-position to the lost nitrogen we obtained the following sequence of mutagenicity (R=substituent): $$R = NH_2 > H > OCH_3 \sim CHO > Cl = control.$$ . The differences in mutagenicity were partly restricted to specific stages of the cycle of spermatogenesis. There was no correlation between mutagenicity and chemical reactivity. The mutagenicity increased proportionally to duration of feeding. The mutagenic activity of the cytostatically ineffective and only extremely weakly reactive p-Bis-(β-chloroethyl)-amino-benaldehyde (C.B. 1077) shows that chemical reactivity tests are not suited for the estimation of the mutagenicity of drugs by routine. In the series of the bifunctional N-lost-cyclophosphamides the mutagenicity decreased in the series B 801>B 518≧B 525 according to the chemical reactivity. The differences between the mutagenic activity of B 801 and the other substances were especially significant in mature spermatozoa. The sensitivity of the stages of the cycle of spermatogenesis was tested by fractionated matings against the mutagenic impulse of the test substances. Generally the observed mutations were due do changes, induced in postmeiotic and meiotic germ cell stages. Mature spermatozoa proved especially sensitive against p-Bis-(β-chloroethyl)-amino-phenylalanine (C.B. 1128), while on the other hand the efficiency of Cytoxan on this stage was relatively weak. The toxicity of the aromatic nitrogen-mustards was neither correlated with the mutagenic activity nor with the chemical reactivity of these compounds. The most active mutagen had the weakest and the weakest mutagen the highest toxicity. Simultaneous application of C.B. 1128 and 1-cysteine led to a drastical decrease of the mutation rate in comparison with the C.B. 1128 control; previous cysteine treatment was ineffective. The feeding of cysteine respectively cysteamine before X-irradiation with 2,000 R respectively 3,000 R had no inhibiting effect on the X-ray induced mutations.