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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 in vivo metabolism of the cis and trans isomers of N-[3,5-3H]nitroso-2,6-dimethylmorpholine (NDMM) was studied in female Fischer rats, Syrian golden hamsters and guinea pigs by analysis of urinary metabolites using high pressure liquid chromatography (HPLC). Animals were treated by gavage with 12 mg/kg body wt. of NDMM, composed of both isomers and 12 microCi/kg body wt. of either of the separated radioactive isomers (cis or trans). Control animals received 12 mg, 12 microCi/kg body wt. NDMM with both isomers labeled in their natural proportion. There was a substantial increase in the excretion of a particular metabolite, 2-(2-hydroxyl-methyl)ethoxy propanoic acid, in the urine of rats, hamsters and guinea pigs 24 h after received the trans isomer (24, 22 and 13% of the total dose excreted, respectively). A minor metabolite was determined to be 2,6-dimethylmorpholine-3-one, another product of alpha-oxidation. The metabolite 1-amino-2-hydroxypropanol was identified, indicating that NDMM was metabolized by both alpha- and beta-oxidation. In all three species, animals administered the cis isomer excreted larger amounts of N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine (HPOP) and N-nitroso-bis(2-hydroxypropyl)amine (BHP) products of beta oxidation, than those treated with the trans isomer. Hamsters and guinea pigs treated with the more carcinogenic cis isomer in these species, also excreted twice as much of two other metabolites than was found in the urine of animals given the trans isomer. The trans isomer of NDMM appeared to be preferentially metabolized by alpha-oxidation and from earlier studies this metabolic pathway seemed to be important in carcinogenesis by NDMM in the rat. The cis isomer might be in a conformation more favorable for beta-oxidation and this pathway may be of primary importance in carcinogenesis by NDMM in hamsters and guinea pigs.
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PMID:Comparative metabolism of the cis and trans isomers of N-nitroso-2,6-dimethylmorpholine in rats, hamsters and guinea pigs. 674 63

Liver microsomes from male Syrian golden hamsters and Sprague Dawley rats metabolize the cis and trans isomers of N-nitroso-2,6-dimethylmorpholine (NNDM) to N-nitroso-(2-hydroxypropyl)(2-oxopropyl)amine (HPOP) as the major product detectable by h.p.l.c. The rates of total metabolism are similar for both the cis and trans isomers; but the cis isomer of NNDM yields greater than 70% of the total product as HPOP while the trans isomer yields HPOP only as a minor product (20-30%) in both hamster and rat. The inability to identify other products could be attributed to alpha-hydroxylation which leads to fragmentation of NNDM and loss of tritium label to water. In order to investigate the possibility of the participation of an alpha-hydroxylation reaction, the metabolism of NNDM fully deuterated at either the 3 and 5 (alpha-d4) or the 2 and 6 (beta-d2) positions was examined and compared to the metabolism of the undeuterated compound (d0). Although the rates of metabolism of all the cis and trans derivatives of NNDM were similar (VMax = 2.13 nmol/min/mg hamster microsomal protein) as determined from measurements of substrate disappearance, the yields of HPOP were different. Maximum HPOP yields were observed with cis alpha-(d4) NNDM (93.9% of the total), followed by cis d0 NNDM (72.3%), trans alpha-(d4) NNDM (60.1%), trans d0 NNDM (30.2%), cis beta-(d2) NNDM (19.5%) and trans beta-(d2) NNDM (8.5%). These results suggest that alpha-hydroxylation is an alternative to beta-hydroxylation. Since the carcinogenic potency of the various deuterium derivatives of NNDM for the Syrian golden hamster parallels their ability to yield HPOP, beta-hydroxylation is closely related to pancreatic carcinogenesis in the hamster. Rat liver microsomal fractions showed the same patterns of HPOP formation to total metabolite yields as hamster liver microsomes with both the cis and trans isomers. However, rates of NNDM metabolism and HPOP formation were 7 times faster with hamster than with rat liver microsomes. Such a difference may be related to the failure of the cis isomer to induce pancreatic cancer in rats.
Carcinogenesis 1984 Aug
PMID:Metabolism of the cis and trans isomers of N-nitroso-2,6-dimethylmorpholine and their deuterated analogs by liver microsomes of rat and hamster. 674 10

Groups of 20 Syrian male golden hamsters were treated by gavage with solutions of the cis and trans isomers of N-nitroso-2,6-dimethylmorpholine in olive oil. Two doses of each isomer were given for the same time and the ratios of the concentrations corresponded with the ratio in the normally prepared mixture, 2 parts cis to 1 part trans. The cis isomer was more potent in inducing tumors of the liver and pancreas than the trans isomer. The effect of replacement of hydrogen with deuterium at the positions alpha and beta to the nitroso function on carcinogenic potency was examined by administering by gavage the respective isotopically labeled compounds to groups of 20 male hamsters. Each labeled sample constituted a mixture of cis and trans isomers in the ratio of approximately 2 to 1, and the dose was identical with that of the unlabeled sample of the nitrosamine. The beta deuterium labeled compound was less carcinogenic and the alpha deuterium labeled compound was more carcinogenic than the unlabeled material. There was not significant difference between the isomers in activation to a bacterial mutagen by pancreas microsomes or in binding to DNA of the pancreas.
Carcinogenesis 1981
PMID:Carcinogenesis in Syrian hamsters by N-nitroso-2,6-dimethylmorpholine, its cis and trans isomers, and the effect of deuterium labeling. 702 78

The cis and trans isomers of nitroso-2,6-dimethylmorpholine (Me2NMOR) have been separated and administered to Fischer 344 rats at doses corresponding to their proportion in the mixture prepared from the commercial amine (approximately 2 cis to 1 trans). The mixture of isomers was given at 2 doses, 50 mg per liter of drinking water and 20 mg per liter. A standard volume of each solution was given (20 ml per day per rat) on 5 days of each week and the animals were treated for the same time at either higher or lower dose levels. Almost all of the animals died with basal cell carcinomas and/or papillomas of the upper gastrointestinal tract. The time at which the rats died with the tumors was used as a measure of carcinogenic potency. Survival of the treated animals was consistently longer at the lower dose of each isomer. It was concluded that the trans isomer of Me2NMOR is a more potent carcinogen in rats than the cis isomer.
Carcinogenesis 1980 Jun
PMID:Comparison of carcinogenesis by two isomers of nitroso-2,6-dimethylmorpholine. 727 83

Nitroso-2,6-dimethylmorpholine (Me2NMOR) was labeled with deuterium in either the alpha or beta positions. Both the deuterium-labeled, and the unlabeled, compounds were administered to female Fischer 344 rats at equimolar concentrations in drinking water. The animals were then allowed to die naturally with tumors. The parent compound and the alpha-d4-labeled derivative were given at 50 mg/liter and 20 mg/liter, while, because of a shortage of the compound, the beta-d2-labeled derivative was given only at 20 mg/liter. Almost all of the animals died with basal cell carcinomas and papillomas of the esophagus; many animals fed the lower doses also had tumors of the nasal cavity and tongue. The rate of death from induced tumors was lower in the alpha-d4-treated group than in those treated with the unlabeled compound (at both dose levels), but was higher in the rats treated with the beta-d2 compound. It appears that deuterium in the alpha positions decreases carcinogenic potency, while deuterium in the beta positions increases it. This suggests that oxidation at the beta carbon atoms is less likely to be involved in esophageal carcinogenesis in the rat by Me2NMOR than is oxidation at the alpha carbon atoms.
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PMID:The effect of deuterium labeling on the carcinogenicity of nitroso-2,6-dimethylmorpholine in rats. 742 26

Initiation activities of endogenously formed N-nitrosobis(2-hydroxypropyl)amine (NBHPA), N-nitrosodiethanolamine (NDELA) and N-nitroso-2,6-dimethylmorpholine (NDMM) were investigated in a modified short-term assay for rat hepatocarcinogenesis. Male Wistar rats were fed 1% bis(2-hydroxypropyl)amine, 0.5% diethanolamine or 0.25% 2,6-dimethylmorpholine in the diet plus 0.3% sodium nitrite in the drinking water. Two weeks after starting the experimental regimen they underwent 2/3 partial hepatectomy and were then maintained on the respective diets for a further week. Following a 2 week recovery period on basal diet rats were subjected to a resistant hepatocyte regimen consisting of 0.02% 2-acetylaminofluorene in the diet for 2 weeks and 1 mg carbon tetrachloride/kg body wt by gavage at the midpoint. Initiation activity was assayed by measuring hepatic foci positive for gamma-glutamyltranspeptidase. Numbers of such foci per cm2 were significantly increased in the groups given the secondary amines together with nitrite compared with values for groups given each precursor or nitrite alone. Further, the numbers of lesions were essentially similar to those found in rats given carcinogenic doses of NBHPA, NDELA and NDMM. The results clearly of demonstrate hepatocyte initiation activities of endogenously formed carcinogens, presumably NBHPA, NDELA and NDMM.
Carcinogenesis 1995 Nov
PMID:Initiation of hepatocarcinogenesis by endogenously formed N-nitrosobis(2-hydroxypropyl)amine, N-nitrosodiethanolamine and N-nitroso-2,6-dimethylmorpholine in rats. 758 78


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