An investigation of the genotoxic effects of N-nitrosomorpholine in mammalian cells.
N-nitrosomorpholine (NMOR) is a well-known hepatocarcinogen. Since this compound is representative of the group of indirect-acting N-nitrosamines, its metabolic activation should be essential. However, the mechanism of NMOR-induced carcinogenesis is still not completely clear. In this paper we tried to further our understanding of the genotoxic effects of NMOR. The central aim of this study was to elucidate to what extent NMOR requires metabolic activation. For evaluation of the mutagenicity of NMOR, V79 cells were used either in the presence or absence of the microsomal S9 fraction in the mutation assay and formation of reactive oxygen/nitrogen species (ROS/RNS) in Caco-2 cells treated with NMOR was measured by a fluorescent assay. A very weak rise of 6-thioguanine resistant mutations was observed in both NMOR-treated model cells, V79/-S9 and V79/+S9. A significant difference between the level of mutations in V79/-S9 and V79/+S9 cells was recorded on the 7th day of expression only. Data obtained by the fluorescent assay confirmed that NMOR caused generation of ROS/RNS. In summary, the presented results showed that NMOR might induce DNA damage not only indirectly by its activation by drug-metabolizing enzymes but also via direct formation of ROS/RNS.
Robichová
Sona
S
Cancer Research Institute, Slovak Academy of Sciences, Vlárska 7, 833 91 Bratislava, Slovak Republic. sona.robichova@savba.sk
Slamenová
Darina
D
Gábelová
Alena
A
Sedlák
Ján
J
Jakubíková
Jana
J
D016604:Aflatoxin B1 / Q000494:pharmacology; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D003114:Colony-Forming Units Assay; D007041:Hypoxanthine Phosphoribosyltransferase / Q000187:drug effects / Q000235:genetics; D008322:Mammals; D008769:Methylnitronitrosoguanidine / Q000494:pharmacology; D009153:Mutagens / Q000633:toxicity*; D009602:Nitrosamines / Q000633:toxicity*
D009153:Mutagens; D009602:Nitrosamines; D008769:Methylnitronitrosoguanidine; C002741:N-nitrosomorpholine; D016604:Aflatoxin B1; D007041:Hypoxanthine Phosphoribosyltransferase