Carcinogenicity of Nitrosothiomorpholine and 1-Nitrosopiperazine In Rats (original) (raw)
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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.
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.
ncrl135-Tumorigenicity of N-Nitrosohexamethyleneimine
Cancer Research 28: 1217-1222 (1968)
A new carcinogen, W-nitrosohexamethyleneimine (W-nitrosoperhydroazepine), was synthesized and given to rats of both sexes. The incidence of mixed malignant liver cell carcinomas and endothelial sarcomas was virtually 100% when the drug was given at 200 mg/liter for 8 weeks, while benign and malig nant epitheliomas of the tongue or esophagus occurred in about 30%. When the drug concentration was 50 mg/liter given con tinuously over the life-span of the animals, the incidence pat tern of tumors in liver and upper alimentary tract was re versed. The possible relevance of the types and distribution of these cancers to interpretations of the mechanism of action is discussed.
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:
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.
Dietary Enhancement of Nitrosamine Carcinogenesis1
Previous studies have shown that a diet high in fat and marginally deficient in lipotropes enhances aflatoxin B] hepatocarcinogenesis and depresses hepatic drug metabolism in rats. In this study we have compared induction of tumors by jV-nitrosodimethylamine, ./V-nitrosodiethylamine, or jV-nitrosodibutylamine in normal or marginally lipotrope-deficient rats fed a high-fat diet. The deficiency significantly enhanced hepatocarcinogenesis by both JV-nitrosodiethylamine and Nnitrosodibutylamine and may have enhanced esophageal carcinogenesis by ./V-nitrosodiethylamine. Induction of tumors by yV-nitrosodimethylamine and jV-nitrosodimethylamine metabolism in vitro in liver slices were not significantly affected by the diet.
Dietary enhancement of nitrosamine carcinogenesis
Cancer research, 1974
Previous studies have shown that a diet high in fat and marginally deficient in lipotropes enhances aflatoxin B] hepatocarcinogenesis and depresses hepatic drug metabolism in rats. In this study we have compared induction of tumors by jV-nitrosodimethylamine, ./V-nitrosodiethylamine, or jV-nitrosodibutylamine in normal or marginally lipotrope-deficient rats fed a high-fat diet. The deficiency significantly enhanced hepatocarcinogenesis by both JV-nitrosodiethylamine and Nnitrosodibutylamine and may have enhanced esophageal carcinogenesis by ./V-nitrosodiethylamine. Induction of tumors by yV-nitrosodimethylamine and jV-nitrosodimethylamine metabolism in vitro in liver slices were not significantly affected by the diet. protein. Before the effects of individual diets were examined, studies were undertaken to compare the effect of the 2 diets on carcinogenesis by other compounds and in other organs in order to determine whether enhancement of carcinogenesis by the deficient diet was specific for AFB!. The 1st group of carcinogens studied was the nitrosamines, which comprise a large group of tumor-inducing compounds in many different organs of expermental animals. They are also found in human foods and are suspected to be a causative factor in human esophageal carcinoma (1, 3,6,8, 10, 24). The carcinogenic effect of the simplest compound, DMN, is susceptible to dietary alteration. Protein deficiency increases the number of renal tumors induced, while depressing induction of hepatic tumors, and decreases the ability of the liver to metabolize DMN (7, 13, 27).
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.
Dietary effects of the pharmacokinetics of three carcinogenic nitrosamines
Toxicology and Applied Pharmacology, 1978
The concentrations of N-nitrosodimethylamine (DMN), N-nitrosodiethylamine (DEN), and N-nitrosodibmylamine (DBN) were monitored as a function of time in the blood and liver of rats fed either a normal diet or a diet marginally deficient in hpotropes. The disappearance of each nitrosamine from the blood showed first-order kinetics. Hepatic clearance of DEN and DBN also followed first-order kinetics, but the time dependence of DMN concentration in liver tissue showed an anomalous behavior. Diet-related differences in the pharmacokinetic data did not explain the variations in carcinogenicity caused by diet. Epidemiological studies have identified a number of well-defined geographical areas in which populations have a greater or smaller than average risk of developing certain cancers and have suggested that, in some cases, nutrients or foods may be the responsible factors (National Cancer Institute/American Cancer Society, 1975; Alcantara and Speckmann, 1976). In the United States one large group with varying degrees of nutritional deficiency consists of people having fatty livers and/or cirrhosis secondary to alcoholism. This group also has an increased risk of developing hepatic or esophageal cancer (Steiner, 1960; Wynder and Bross, 196 1). Severe lipotrope deficiency in rats provides a good experimental model for nutritional or alcoholic liver disease, but this condition does not support the longevity or weight gain necessary for carcinogenesis studies. A diet that is only marginally deficient in lipotropes, niacin, and amino acids and high in fat, however, supports nearly normal weight gain and enhances induction of hepatic, esophageal, or colon tumors by aflatoxin Bi (AFBJ, jV-nitrosodiethylamine (DEN), N-nitrosodibutylamine (DBN), N-2-fluorenylacetamide (AAF), 1,2-dimethylhydrazine (DMH), and 3,3-diphenyl-3-(dimethylcarbamoyl)1-propyne (DDCP) (Rogers and Newberne, 197la, 1973a, 1975; Rogers et aI., 1974; Rogers, 1975). Induction of bladder or gastric tumors by DBN, ZV-[4-(5nitro-2-fury&2-thiazolyllformamide (FANFT), DDCP, or N-methyl-N'-nitro-ZV-nitrosoguanidine (MNNG) and induction of liver tumors by iV-nitrosodimethylamine (DMN)
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.