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Query: CAS:141-91-3 (2,6-dimethylmorpholine)
 46 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of continuous week-long administration of the three pancreatic carcinogens N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine (HPOP), N-nitrosobis(2-hydroxypropyl)amine (BHP), and cis-N-nitroso-2,6-dimethylmorpholine (cis-NNDM), by a s.c. implanted osmotic pump, was examined in Syrian hamsters. HPOP at total doses of 220-250 mg/kg body weight induced ductal adenocarcinomas in the pancreas (41%), and cholangiomas (18%) and cholangiocarcinomas (18%) in the liver, 25 weeks following the initiation of treatment. Higher doses of HPOP resulted in severe hepatic injury and increased mortality (LD50 = 280 mg/kg). Cis-NNDM and BHP were less toxic than HPOP and induced pancreatic lesions at doses of 950 mg/kg. These data document that a week-long schedule of continuous administration of HPOP for the induction of pancreatic cancer compares favorably with those involving weekly injections. Application of this model to study the effect of dietary protein in HPOP-induced carcinogenicity showed that the number of cystic, intermediate and tubular complexes in the pancreas was significantly higher in animals fed a 20% as compared to an 8% protein diet 2 weeks prior to HPOP administration. Furthermore, the incidence of pancreatic adenocarcinomas and in situ carcinomas was only 13% in the hamsters fed the low-protein diet as compared to 46% in those fed the high-protein diet.
Carcinogenesis 1989 Apr
PMID:Carcinogenicity of N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine, N-nitrosobis(2-hydroxypropyl)amine and cis-N-nitroso-2,6-dimethylmorpholine administered continuously in the Syrian hamster, and the effect of dietary protein on N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine carcinogenesis. 264 66

The mutagenic potential of nine carcinogenic N-nitrosopropylamines was examined by Ames preincubation assay using liver 9000 g supernatant (S9) fractions from female rats and male hamsters and mice for metabolic activation. N-Nitrosobis(2-hydroxypropyl)amine, N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine, N-nitrosobis(2-oxopropyl)amine, N-nitrosobis(2-acetoxypropyl)amine, N-nitroso-2,6-dimethylmorpholine, N-nitrosomethyl(2-hydroxypropyl)amine, N-nitrosomethyl(2-oxopropyl)amine, N-nitroso(2,3-dihydroxypropyl)(2-hydroxypropyl)amine and N-nitrosomethyl(2,3-dihydroxypropyl)amine all showed positive mutagenicity in strain TA100 in the presence of liver S9 from three animal species pretreated with polychlorinated biphenyls or phenobarbital (PB). The S9-mediated mutagenicity of these N-nitrosamines was almost completely diminished by the removal of NADP+ from the assay system. All the activities were considerably decreased by preincubation in an atmosphere of carbon monoxide or adding cytochrome c to the S9 mixture. Metyrapone considerably inhibited mutagenicity, whereas 7,8-benzoflavone was totally lacking this effect. These results demonstrate a correlation between the mutagenicity of nine N-nitrosopropylamines mediated by liver S9 from three animal species and their known carcinogenicity in rodent in vivo experiments, and that the PB-inducible major cytochrome P-450 is selectively involved in the mutagenic activation. A relationship between mutagenic potencies of the N-nitrosamines and their known carcinogenic potencies in rats and hamsters is discussed.
Carcinogenesis 1986 Mar
PMID:Mutagenic activation of carcinogenic N-nitrosopropylamines by liver S9 fractions from mice, rats and hamsters: evidence for a cytochrome P-450-dependent reaction. 351 16

A number of N-nitroso compounds and an azoxyalkane have been labeled with deuterium in various positions and have been administered to rats, hamsters, or mice in parallel with the unlabeled compounds. The treatments with the labeled and analogous unlabeled compounds were equimolar and for the same time. Mortality rates from tumors and tumor incidences were compared between deuterium-labeled and the unlabeled analogs. In many cases more than one dose level was used for the comparisons. An increased rate of mortality from tumors or an increased incidence of induced tumors was considered an index of increased potency of one treatment compared with the other. Using these criteria deuterium in the alpha positions of nitrosodimethylamine, nitrosomorpholine, nitrosoheptamethyleneimine, and nitrosoazetidine reduced carcinogenic potency compared with the unlabeled compounds. This indicated that cleavage of a carbon-hydrogen bond in the alpha position was a rate-limiting step in carcinogenesis by these nitrosamines. In both nitrosomethylethylamine and nitroso-2,6-dimethylmorpholine, the presence of deuterium at different positions increased or decreased carcinogenic potency, suggesting that competition for oxidation between these sites might be the determining factor in activation of the molecule. This also applied to nitrosomethyl-n-butylamine and nitrosomethyl-phenylethylamine with deuterium at the methyl group or at the alpha carbon of the butyl or phenylethyl groups, and to azoxymethane with deuterium in the 1-methyl or 4-methyl group. In nitrosomethylcyclohexylamine, nitrosomethyl-n-dodecylamine, and dinitroso-2,6-dimethylpiperazine there was no detectable effect of deuterium on carcinogenic potency, suggesting that the conditions did not provide sufficient sensitivity for detection of an isotope effect, or that oxidation at the alpha carbon was not a rate-limiting step in carcinogenesis by these molecules.
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PMID:Deuterium isotope effects in carcinogenesis by N-nitroso compounds. 353 43

Lung carcinogenesis by a single intraperitoneal injection of N-nitrosobis(2-hydroxypropyl)amine (NDHPA) and related compounds was studied in male Wistar rats. NDHPA, N-nitrosomethyl(2-hydroxypropyl)amine (NMHPA), N-nitrosobis(2-oxopropyl)amine (NDOPA), N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine (NHPOPA) and N-nitroso-2,6-dimethylmorpholine (NDMMOR) induced high incidences of lung neoplasms in rats. The formation of NDHPA, NDMMOR and NMHPA in the stomach of rats treated with precursor amines and sodium nitrite was detected by high-performance liquid chromatography (HPLC).
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PMID:Lung carcinogenesis by N-nitrosobis(2-hydroxypropyl)amine-related compounds and their formation in rats. 367 77

The experiments reported here were undertaken to ascertain whether the principle of the selection and rapid emergence of carcinogen-initiated cells based on their resistance to cytotoxicity demonstrated in rat liver is applicable to hamster pancreas. Hamsters injected with a single dose of 70 mg/kg body weight of the pancreatic carcinogen, N-nitrosobis(2-oxopropyl)amine, were subjected to pancreatic injury and regeneration induced by DL ethionine followed by methionine rescue while on a continuous daily regimen of 10 mg/kg body weight of N-nitroso-2,6-dimethylmorpholine by gavage. Randomly selected animals were killed weekly from the 4th week following the induction of regeneration through the 10th week. This carcinogenic schedule significantly decreased the time of emergence of cell injury, cell death, and proliferative, preneoplastic, and neoplastic lesions of the exocrine pancreas. Carcinoma in situ and invasive adenocarcinoma of pancreatic ducts appeared during the 7th and 8th week after induction of pancreatic regeneration, earlier than results obtained with multiple dose carcinogenesis experiments.
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PMID:Pancreatic lesions induced by a single dose of N-nitrosobis(2-oxopropyl)amine and selection by resistance to cytotoxicity. 378 14

N.m.r. spectroscopy demonstrates that N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine (HPOP) exists as a mixture of four isomers, A, B, C and D, the equilibrium ratios of which are 57:8:16:19, respectively, at 25 degrees C. Two of these isomers, A and B, are rotomers of the open chain conformer, while the other two, C and D, are rotomers of the ring tautomer of HPOP and are derived from A and B, respectively, via an intramolecular cyclization reaction. A syn orientation of the nitroso and carbonyl groups favors an open chain configuration (isomer A), while an anti orientation favors cyclization of the molecule (isomer D). Two forms of HPOP (I and II) which are mixtures of isomers A and C, and D and B, respectively were separated chromatographically. These two forms interconvert to each other. The first rate order constants for the interconversion reactions were determined to be 4.7 X 10(-3) and 12.8 X 10(-3)/min, respectively. During these reactions isomers A and D interconvert via the intermediate formation of isomer C. This suggests that rotomerization of C and D is thermodynamically more favorable than rotomerization of their open-chain tautomers A and B, and suggests an intramolecular interaction between the carbonyl and nitroso groups. Isomers A and D are formed during the metabolism of N-nitrosobis(2-oxopropyl)amine (BOP) and cis N-nitroso-2,6-dimethylmorpholine (NNDM), respectively, by hamster liver microsomes and NADH or NADPH. The stereo-specificity of reduction of BOP and the hydroxylation of cis NNDM results in the formation of two slowly interconvertible isomers of HPOP. This, in combination with a possible different metabolic fate of the cyclic and open tautomers of this compound, may have a significant impact on the mechanism of activation of pancreatropic nitrosamines which share HPOP as a common metabolite.
Carcinogenesis 1987 Jan
PMID:Structural relationships of pancreatic nitrosamine carcinogens. 380 97

Mutagenic potential of carcinogenic N-nitrosopropylamines was examined by the Ames's liquid incubation assay, using rat liver 9000 g supernatant (S9) fraction for metabolic activation. N-Nitrosobis(2-hydroxypropyl)amine, N-nitroso(2-hydroxypropyl)-(2-oxopropyl)amine (HPOP), N-nitrosobis(2-oxopropyl)amine (BOP), N-nitrosobis(2-acetoxypropyl)amine, N-nitroso-2,6-dimethylmorpholine, N-nitrosomethyl-(2-hydroxypropyl)amine and N-nitrosomethyl(2-oxopropyl)amine all showed positive mutagenicity in strain TA100 in the presence of liver S9 while being negative in strain TA98. With the exception of HPOP and BOP, which were also mutagenic in TA100 without S9 metabolic activation, these N-nitrosopropylamines required the presence of microsomes as a source of enzymes as well as NADP+ as a cofactor for mutagenic activation. Treatment of rats with polychlorinated biphenyls or phenobarbital (PB) resulted in a marked increase in the ability of S9 to activate the seven N-nitrosamines tested whereas 3-methylcholanthrene (3-MC) induction was not effective. All the mutagenic activities were considerably decreased by preincubation in an atmosphere of either carbon monoxide or nitrogen gas or by adding cytochrome c to the S9 mixture. Metyrapone, a specific inhibitor of PB-inducible major cytochrome P-450, considerably inhibited mutagenicity, whereas 7,8-benzoflavone, a specific inhibitor of 3-MC-inducible major cytochrome P-448, was totally lacking this effect. These results demonstrate a correlation between rat liver S9 dependent mutagenicity of six N-nitrosopropylamines and their known carcinogenicity in rat in vivo experiments, and that the PB-inducible major cytochrome P-450 is involved in the mutagenic activation. BOP was also shown to be activated by extrahepatic (lung, kidney, pancreas) tissue S9, blood S9 and bovine serum albumin (BSA) to the extent of 50% of that activity obtained with liver S9. A possible mechanism of BSA-mediated activation of BOP is discussed.
Carcinogenesis 1985 Mar
PMID:Mutagenic activation of carcinogenic N-nitrosopropylamines by rat liver: evidence for a cytochrome P-450 dependent reaction. 388 71

The alkylation of nucleic acids of the liver of rats and Syrian hamsters was measured in relation to carcinogenesis by a number of nitrosamines and azoxyalkanes, most of which induce tumors of the liver in both species following chronic treatment. Two compounds, nitroso-2,6-dimethylmorpholine and nitrosobis(2-hydroxypropyl)amine were not liver carcinogens in rats, but did induce liver tumors in hamsters; there was much less alkylation by these compounds in the rat than in the hamster. In both rats and hamsters, azoxymethane produced a greater extent of alkylation, both at N-7 and O-6 guanine, than did nitrosodimethylamine, although the former is no more potent than the latter as a carcinogen in either species. Both methyl groups of azoxymethane gave rise to N-7 methylation. Nitrosobis(2-oxopropyl)amine (BOP) and nitroso(2-hydroxypropyl) (2-oxopropyl)amine (HPOP) produced considerable methylation of liver nucleic acids in both species, comparable with that by nitrosodimethylamine, and they induce liver tumors in both rats and hamsters. However, in male rats the extent of alkylation by BOP was much smaller than in females and no O-6-methylation was detected in the former; this correlates with the failure of BOP to induce liver tumors in male rats by gavage, whereas liver tumors are induced in females.
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PMID:The metabolism and cellular interactions of some aliphatic nitrogenous carcinogens. 391 87

For examination of metabolic interrelationships in carcinogenesis between N-nitroso-2,6-dimethylmorpholine, N-nitrosobis(2-oxopropyl)amine (CAS: 60599-38-4), N-nitrosobis(2-hydroxypropyl)amine (CAS: 53609-64-6), and N-nitroso(2-hydroxypropyl) (2-oxopropyl)amine, each was given to a separate group of 20 female Syrian golden hamsters by gavage. All four compounds induced tumors of the pancreatic duct and lung tumors, but the incidences varied from one compound to another. In addition, N-nitrosobis(2-oxopropyl)amine and N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine induced many hepatocellular and cholangiocellular neoplasms, which the other two compounds did not. On the basis of short time to death with tumors and the relatively low total dose administered, N-nitrosobis(2-oxopropyl) amine appeared to be the most potent carcinogen in the hamster among the four. N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine was next in potency but was considerably weaker than N-nitrosobis(2-oxopropyl)amine. N-Nitroso-2,6-dimethylmorpholine, which was similar in potency to N-nitroso(2-hydroxypropyl) (2-oxopropyl)amine, however, did not induce a significant incidence of liver tumors of any type; and N-nitrosobis(2-hydroxypropyl) amine was considerably less potent than the other three compounds. These results did not support the opinion of N-nitroso(2-hydroxypropyl) (2-oxopropyl)amine as the proximate carcinogenic metabolite of all three compounds in the Syrian hamster but instead suggested that these compounds might have acted through formation of different and yet unknown carcinogenic intermediates.
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PMID:Comparison of the carcinogenic effectiveness of N-nitrosobis(2-hydroxypropyl)amine, N-nitrosobis(2-oxopropyl)amine, N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine, and N-nitroso-2,6-dimethylmorpholine in Syrian hamsters. 658 51

Liver preparations from Syrian golden hamsters catalyze the metabolism of the pancreatic carcinogen N-nitroso-2,6-dimethylmorpholine largely to N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine (HPOP). This reaction is catalyzed by a mixed-function oxidase in the presence of reduced nicotinamide adenine dinucleotide phosphate and oxygen at a rate of 3.8 nmol/min/mg of protein, and it is inhibited by known cytochrome P-450-specific inhibitors. A second potent pancreatic carcinogen N-nitrosobis(2-oxopropyl)amine (BOP) is converted to HPOP by hamster liver in which two enzyme systems appear to be involved. The first is a reductase associated with microsomes which reduces BOP to HPOP in the presence of reduced nicotinamide adenine dinucleotide at a rate of 9.1 nmol/min/mg of protein. The second enzyme is a cytosolic one which catalyzes the same reaction at a slower rate (2.3 nmol/min/mg of protein) and is more effective with reduced nicotinamide adenine dinucleotide phosphate as cofactor. Based on the amount of protein in hepatic cytosol and endoplasmic reticulum, the two enzymes may be involved to a similar extent in the reduction of BOP to HPOP in the liver. Pancreas, on the other hand, lacks the microsomal reductase for BOP but contains a cytosolic enzyme which catalyzes its reduction in the presence of reduced nicotinamide adenine dinucleotide phosphate at a rate of 0.35 nmol/min/mg of protein. Since both pancreatic carcinogens N-nitroso-2,6-dimethylmorpholine and BOP are metabolized to HPOP in the liver at rates much higher than those observed in the target organ pancreas, it is suggested that the liver may play an important role in pancreatic carcinogenesis in the hamster by these compounds.
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PMID:Metabolism of pancreatic carcinogens N-nitroso-2,6-dimethylmorpholine and N-nitrosobis(2-oxopropyl)amine by microsomes and cytosol of hamster pancreas and liver. 664 May 29


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