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Mutagenicity of epoxides
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consecutive days with a dose of 300 mg/kg disulfiram, an aldehyde dehydrogenase inhibitor. On the third day 1200 mg/kg ethyl alcohol was given atse orally. 30 min later the rats were sacrificed, their livers homogenized, centrifuged and the supernatant incubated with E. coli cells for 30 rain. No mu~ao genic effect of a single treatment of alcohol or its metabolites was detected in the liver extract of rats with dose comparable to human consumption even in aldehyde dehydrogenase inhibited state. 82 R. Jung, H.R. Glatt, D. Beerman and F. Oesch, Institute of Pharmacology, University of Mainz, D-6500 Mainz (Federal Republic of Germany)
Mutagenicity o f epoxides A broad variety of environmental and endogenous c o m p o u n d s are metabolized by mammals via epoxides, which are electrophilically reactive. Potent mutagenic activity has been shown for K-region and bay-region epoxides of polycyclic aromatic hydrocarbons. Apart from these relatively few epoxides have so far been investigated for mutagenicity. In the present study, we tested 70 epoxides of widely different structure for their direct mumgenicity in Salmonella typhimurium strains° One series of c o m p o u n d s was derived from benzene and its hydrogenated derivatives, which are structural elements of many drugs. We investigated various mono-, d i - a n d triepoxides of these monocyclic hydrocarbons. Most o f them were weakly to moderately active. Only benzene oxide (which is unstable in aqueous solution) and cis-benzene trioxide turned o u t to be non-mutagenic. Amongst the tested epoxides were also 11 steroids, 21 pharmaceuticals or drug metabolites and 5 endogenous compounds. Of these only the cytostatic drug ethoglucid showed a marked mutagenicity, whereas all other c o m p o u n d s were negative or more than 100 000-fold less mutagenic than the reference c o m p o u n d benzo [a]pyrene 4,5-oxide. In our study all bulky, non-planar epoxides were n o t mutagenic. In contrast, most of the smaller epoxides were (relatively weak) mutagens, particularly if they had only one or t w o substituents on the oxirane ring. This work was supported b y DFG. 83 A. Kappas and N. Demopoulos. Biology Department, Nuclear Research Cen~er "Democritus", Athens, and Department of Genetics, University at Patras, Patras (Greece) Recombinogenicity of the antitumor antibiotic bleomycin in Aspergillus nidulans Bleomycin, an antibiotic and antineoplastic drug, which inhibits D N A synthesis and causes several types o f chromosomal aberrations, was found to increase mitotic recombination in AspergiUus nidulans prototrophic diploid strains heterozygous for spore color and several nutritional markers, shown as
consecutive days with a dose of 300 mg/kg disulfiram, an aldehyde dehydrogenase inhibitor. On the third day 1200 mg/kg ethyl alcohol was given atse orally. 30 min later the rats were sacrificed, their livers homogenized, centrifuged and the supernatant incubated with E. coli cells for 30 rain. No mu~ao genic effect of a single treatment of alcohol or its metabolites was detected in the liver extract of rats with dose comparable to human consumption even in aldehyde dehydrogenase inhibited state. 82 R. Jung, H.R. Glatt, D. Beerman and F. Oesch, Institute of Pharmacology, University of Mainz, D-6500 Mainz (Federal Republic of Germany)
Mutagenicity o f epoxides A broad variety of environmental and endogenous c o m p o u n d s are metabolized by mammals via epoxides, which are electrophilically reactive. Potent mutagenic activity has been shown for K-region and bay-region epoxides of polycyclic aromatic hydrocarbons. Apart from these relatively few epoxides have so far been investigated for mutagenicity. In the present study, we tested 70 epoxides of widely different structure for their direct mumgenicity in Salmonella typhimurium strains° One series of c o m p o u n d s was derived from benzene and its hydrogenated derivatives, which are structural elements of many drugs. We investigated various mono-, d i - a n d triepoxides of these monocyclic hydrocarbons. Most o f them were weakly to moderately active. Only benzene oxide (which is unstable in aqueous solution) and cis-benzene trioxide turned o u t to be non-mutagenic. Amongst the tested epoxides were also 11 steroids, 21 pharmaceuticals or drug metabolites and 5 endogenous compounds. Of these only the cytostatic drug ethoglucid showed a marked mutagenicity, whereas all other c o m p o u n d s were negative or more than 100 000-fold less mutagenic than the reference c o m p o u n d benzo [a]pyrene 4,5-oxide. In our study all bulky, non-planar epoxides were n o t mutagenic. In contrast, most of the smaller epoxides were (relatively weak) mutagens, particularly if they had only one or t w o substituents on the oxirane ring. This work was supported b y DFG. 83 A. Kappas and N. Demopoulos. Biology Department, Nuclear Research Cen~er "Democritus", Athens, and Department of Genetics, University at Patras, Patras (Greece) Recombinogenicity of the antitumor antibiotic bleomycin in Aspergillus nidulans Bleomycin, an antibiotic and antineoplastic drug, which inhibits D N A synthesis and causes several types o f chromosomal aberrations, was found to increase mitotic recombination in AspergiUus nidulans prototrophic diploid strains heterozygous for spore color and several nutritional markers, shown as