Carcinogenicity of Nitrosothiomorpholine and 1-Nitrosopiperazine In Rats (original) (raw)
Tumorigenicity of five cyclic nitrosamines in MRC rats
Zeitschrift f�r Krebsforschung und Klinische Onkologie, 1972
Five cyclic nitrosamines have been fed to groups of 30 MRC rats at a concentration of 100 rag/liter in drinking water. Nitroso-3-pyrroline produced only tumors of the liver, and was the weakest carcinogen of the five. Nitrosopiperidine induced tumors of liver, esophagus and respiratory tract. Nitrosomorpholine induced tumors of liver and the nasal cavity. Nitrosoheptamethyleneimine induced squamous tumors of lung, and tumors of the esophagus and trachea and was the most potent carcinogen of the five. Dinitrosopiperazine induced tumors of the nasal cavity. The reasons for the pronounced organ specificities of these nitrosamines are discussed. Tumorerzeugende Wirkung von ffinf cyclischen Nitrosaminen bei MRC-Ratten Zusammen/assung. Gruppen von je 30 MRC-Ratten wurden in einer Konzentration von 100 mg/1 im Trinkwasser Nitrosamine gegeben. Es entstanden nach Nitroso-3-pyrrolin, dem schw~chsten Cancerogen, nur Lebertumoren, nach Nitrosopiperidin Tumoren yon Leber, Sl3eiscrShre und Respirationstrakt, nach Nitrosomorpholin Tumoren von Leber und Nasen-hShle, nach Nitrosoheptamethylenimin, dcm st/irksten Carcinogen, Plattenepitheltumoren der Lunge und Tumoren yon SpeiserShre und Trachea, nach Dinitrosopiperazine Tumoren der NasenhShle. Die Griinde fiir die ausgcsprochene Organspezifit/it dieser Nitrosoamine werden bcsproehcn.
Carcinogenicity of N-nitrosopyrrolidine: Dose-response study in rats
Zeitschrift f�r Krebsforschung und Klinische Onkologie, 1977
Results from a dose-response study in rats are reported, in which daily oral doses of 10, 3, 1, and 0.3 mg/kg bodyweight/day respectively were administered. The three highest dose levels resulted in incidences of liver cancer of 46, 84, and 32% respectively. In the lowest dose group (0.3 mg/kg! day) no statistically significant increase in tumor rate compared to untreated controls was found. Zusammenfassung: Ergebnisse einer Dosis-Wirkungs-Untersuchung an Ratten werden berichtet, bei welcher tiigliche orale Dosen yon 10, 3, 1 bzw. 0,3 mg/kg/Tag gegeben wurden. Bei den drei hiSchsten Dosis-Gruppen ergaben sich Leber-Krebs-Raten von 46, 84 bzw. 32%. In der Dosis-Gruppe mit 0,3 mg/kg/Tag konnte keine statistisch signifikante Erh/Shung der Tumorrate im Vergleich zu unbehandelten Kontrollen beobachtet werden.
Dose- and Sex-related Carcinogenesis by N-Bis(2-hydroxypropyl)nitrosamine in Wistar Rats
Cancer Science, 2000
An initiation-promotion medium-term bioassay for detection of chemical carcinogens, developed in the male F344 rat, uses 0.1% N-bis(2-hydroxypropyl)nitrosamine (DHPN) among five genotoxic chemicals for the initiation of carcinogenesis in multiple organs. To establish this bioassay in the Wistar strain, the effects of two dose levels of DHPN were evaluated on the main DHPN rat target organs: lung, thyroid gland, kidneys and liver. Four groups of male and female animals were studied: Control-untreated group; Multi-organ initiated group (also referred to as DMBDD, based on the initials of the five initiators)-treated sequentially with N-diethylnitrosamine (DEN, i.p.), Nmethyl-N-nitrosourea (MNU, i.p.), N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN, drinking water), N, N′ ′ ′ ′-dimethylhydrazine (DMH, s.c.) and DHPN (drinking water) for 4 weeks; a third group treated with 0.1% DHPN in drinking water for 2 weeks and the last group treated with 0.2% DHPN in drinking water for 4 weeks. The animals were sacrificed after 30 weeks. DHPN at 0.2% induced preneoplasia in the liver and kidneys of rats of both sexes, the number and area of the putative preneoplastic liver glutathione S-transferase-positive hepatocyte foci being significantly increased in these animals. It also induced benign and malignant tumors in female and in male rats. However, there was no relationship between the increased incidence of preneoplastic lesions and tumor development in the 0.2% DHPN-exposed groups of both sexes. DHPN at 0.1% induced only a few preneoplastic lesions in the liver and kidney and no tumors in both male and female rats. A clear dose and sex-related carcinogenic activity of DHPN was registered, although Wistar rats of both sexes showed a relative resistance to the carcinogenic activity of this compound.
Carcinogenic effects of N-ethyl-N-hydroxyethylnitrosamine and its metabolites in rats and mice
Cancer Letters, 1999
N-ethyl-N-hydroxyethylnitrosamine (EHEN), a member of the nitrosamine class of carcinogens induces renal cancer. However, since very little is known about the metabolic products of EHEN and their effects, these were investigated in rats and mice. EHEN, N-ethyl-N-formylmethylnitrosamine (EFMN) and N-ethyl-N-carboxymethyl-nitrosamine (ECMN) were administered in the drinking water for 2 weeks and the animals were then maintained until sacri®ce at week 32. The urine of the rats was collected over the 2-week exposure period and analyzed by HPLC. The results showed that EHEN but not EFMN or ECMN induces tumors in the kidneys of rats. In mice the lungs were targeted not only by the parent compound but also by both metabolites. The ®ndings suggest that the kidney is the most susceptible organ to EHEN effects in the rat while the lung is the most susceptible organ in mice. These results are consistent with inter-species variation in the metabolism of xenobiotics.
An investigation of the genotoxic effects of N-nitrosomorpholine in mammalian cells
Chemico-Biological Interactions, 2004
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.
Effects of low dose mixtures of four N-nitroso compounds on hepatic foci development in the rat
Cancer Letters, 1996
Potential synergism between four N-nitroso compounds (nitrosomorpholine, nitrosodimethylamine, nitrosodiethanolamine, nitroso-oxazolidine) in rat liver carcinogenesis was examined in the medium-term bioassay. Mage F344 rats were initially given diethylnitrosamine (DEN, 200 mg/kg, ip) and beginning 2 weeks later received test chemicals for 6 weeks individually at a full or l/4 dose of that proven to be carcinogenic individually or in combination. All animals ware subjected to partial hepatectomy at week 3 and killed at week 8. Induction of immunohistochemically-demonshated glutathione Stransferase placental form (GSTP) positive foci was evaluated. The numbers and size of GST-P positive foci were significantly higher than the control levels by the treatment with each nitrosamine at full (l/l) and one quarter doses (114), excepting nitrosodiethanolamine and by combination of the four chemicals at l/4 and l/16. Because the dose-response curves were considered non-linear for most nitrosamines, synergistic effects were not apparent for the l/4 mixture. In~~st~~~, however, the values for rats treated with these four chemicals in combination at the l/4 dose level were almost the same as the average of four individual treatments at the full dose, and those for the l/16 dose mixture were almost the same as the average of l/4 individual treatment groups. These results indicate that these nitrosamines worked additively, rather than synergistically, in rat liver carcinogenesis.
Carcinogenesis and nucleic acid alkylation by some oxygenated nitrosamines in rats and hamsters
Chemico-Biological Interactions, 1988
A comparison has been made of the carcinogenic effects of nitroso-2,6dimethylmorpholine and several hydroxylated acyclic nitrosodialkylamines derived from it or related to it in rats and Syrian hamsters. In rats nitrosodimethylmorpholine was the most potent, inducing mainly esophageal tumors. Nitrosodiethanolamine was the weakest of the five nitrosamines in both rats and hamsters. Tumors of the pancreas ducts were induced by four of the five compounds, but only in hamsters, and esophageal tumors appeared only in rats. Most of the nitrosamines induced tumors of liver and lung in both rats and hamsters. A study of alkylation of nucleic acids of the liver following treatment of rats and hamsters with the radiolabeled nitrosamines showed that nitrosodiethanolamine alkylated liver nucleic acids in rats to only a very small extent. The other four nitrosamines all gave rise to 7-methylation and 06-methylation of guanine residues in DNA of hamster liver and all but nitrosodimethylmorpholine in rat liver DNA, which corresponded quite well with the induction of liver tumors in the two species. Quantitatively, however, there was not a good correlation between liver DNA alkylation and the potency of the nitrosamine in inducing tumors.
Journal of Cancer Research and Clinical Oncology, 1984
Three asymmetric nitrosamines related to nitrosobis-(2-oxopropyl)-amine (BOP) were given to female F 344 rats in drinking water to assess the significance of other alkyl groups on the carcinogenic expression by the 2-oxopropyl group. Nitroso-oxopropylethanolamine (OPE) was weakly carcinogenic, leading to little life-shortening and to induction of tumors (most of them liver neoplasms) in less than half of the treated animals. BOP under these conditions induced a high incidence of hepatocellular carcinomas and hemangiosarcomas of the liver together with lung adenomas in most animals. At the same dose rate nitrosohydroxypropyl-oxopropylamine (HPOP) induced hepatocellular carcinomas, lung carcinomas, and carcinomas of the esophagus with a high incidence; life-shortening was greater with HPOP than with BOP. At a higher dose rate HPOP again induced a high incidence of esophageal carcinomas, and of liver neoplasms, but more animals had hemangiosarcomas than hepatocellular carcinomas. Nitrosodihydroxypropyl-oxopropylamine (DHPOP) increased the mortality rate due to tumors by much more than the other three compounds, but induced mainly tumors of the upper gastrointestinal tract and no neoplasms in the liver. These results do not support the concept that BOP acts through reduction to HPOP, but suggest rather that the nature of the substituents other than 2-oxopropyl in the analogs of BOP has a * Present address:
The carcinogenic effect of ? oxidized dipropylnitrosamine in mice
Zeitschrift f�r Krebsforschung und Klinische Onkologie, 1978
The chronic effect of 2-HPPN and 2-OPPN was examined in mice. Subcutaneous treatment led to neoplasms in the respiratory tract and liver. Tumor localisation, incidences and types were similar in both treatment groups, and a dose response relationship was observed. The data do not allow us to explain unequivocally the effect of DPN, the parent compound of 2-HPPN 1 and 2-OPPN 1.