The rat-liver carcinogen N-nitrosomorpholine initiates unscheduled DNA synthesis and induces micronuclei in the rat liver in vivo.
Alkylation of DNA is generally accepted as the primary event in the carcinogenicity of nitrosamines. However, the cyclic nitrosamine N-nitrosomorpholine (NMOR), a potent rat hepatocarcinogen, has been reported as binding at very low levels to the liver DNA of treated rats. This led us to investigate the activity of NMOR in two in vivo rat-liver genotoxicity assays--for the induction of unscheduled DNA synthesis (UDS) and the production of micronucleated hepatocytes in the liver micronucleus assay (LMN). Rats treated with oral doses of NMOR (10-200 mg/kg) gave a positive liver UDS response either 2.5 h or 12 h after dosing. Similarly, treatment with oral doses of NMOR (10 or 100 mg/kg) followed by mitogenic stimulation with 4-acetylaminofluorene (4AAF) resulted in high incidences of micronucleated hepatocytes in the LMN assay. These data confirm that the genotoxicity reported for NMOR in vitro can be reproduced in vivo and that NMOR interacts with liver DNA of treated rats. Earlier reports of only very weak binding of radiolabelled NMOR to rat liver DNA in vivo are discussed within the context of these data.
Ashby
J
J
ICI Central Toxicology, Macclesfield, Cheshire, Great Britain.
Lefevre
P A
PA
D000818:Animals; D004247:DNA / Q000096:biosynthesis; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects*; D008099:Liver / Q000187:drug effects*; D015162:Micronucleus Tests; D009602:Nitrosamines / Q000633:toxicity*; D051381:Rats
D009602:Nitrosamines; C002741:N-nitrosomorpholine; D004247:DNA