Genotoxicity of 1- and 2-nitropropane in the rat.
2-Nitropropane (2-NP) is a rat liver carcinogen, whilst the 1-isomer is non-carcinogenic in rodents. Although DNA repair tests in the rat liver discriminated clearly between the carcinogenic and the non-carcinogenic isomer, uniformly negative results have been published for the mouse bone marrow micronucleus test (BMMN test) with both isomers. Therefore, the latter assay did not discriminate between the carcinogenic and the non-carcinogenic isomer. To investigate whether this is due to endpoint specificity or organospecificity of 2-NP, studies were carried out in the rat in which micronucleus induction (bone marrow and liver) and unscheduled DNA synthesis (UDS) induction (liver) were measured after oral treatment with either nitropropane isomer. 2-NP induced UDS in the liver whilst the 1-isomer was negative, thus confirming the published studies. In the BMMN test, occasional small increases in the incidence of micronuclei were found for both compounds, but results were interpreted as negative after considering the control background data and the lack of reproducibility. By contrast, the liver micronucleus test revealed a clastogenic effect of 2-NP in the liver. This indicates that 2-NP induces chromosome aberrations as well as DNA repair in vivo, but it seems to act organospecifically. For 1-NP a slightly increased incidence of micronuclei was found in the liver, which was accompanied by a markedly increased mitotic index. It therefore remains questionable as to whether this increased micronucleus frequency for 1-NP is an indicator of a clastogenic effect, or whether it is caused by an increased cell proliferation induced by 1-NP. Consequently, it is too early to conclude whether the liver micronucleus assay is able to discriminate between the carcinogenic and non-carcinogenic isomer. However, the results provide further evidence that bone marrow assays are insufficient for the detection of all genotoxic carcinogens in vivo. This indicates the need for analysing a second tissue, particularly when negative bone marrow results have been obtained with in vitro genotoxins.
George
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E
Genetic and Reproductive Toxicology Department, Glaxo Group Research, Ltd, Ware, Herts, UK.
Burlinson
B
B
Gatehouse
D
D
D000473:Alkanes / Q000633:toxicity*; D000818:Animals; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology; D002273:Carcinogens / Q000633:toxicity; D004261:DNA Replication / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D015162:Micronucleus Tests; D009153:Mutagens / Q000633:toxicity*; D009595:Nitroparaffins / Q000633:toxicity*; D011407:Propane / Q000031:analogs & derivatives* / Q000633:toxicity; D051381:Rats; D011919:Rats, Inbred Strains; D012016:Reference Values; D013329:Structure-Activity Relationship
D000473:Alkanes; D002273:Carcinogens; D009153:Mutagens; D009595:Nitroparaffins; C035314:1-nitropropane; C016617:2-nitropropane; D011407:Propane