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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

N-Nitramines are biologically active compounds of environmental significance. In this study the suggested bioactivation of N- nitrodimethylamine via oxidation at the methyl-group was confirmed, as was indicated by formaldehyde liberation. N- Nitrodimethylamine and formaldehyde as well as the suggested metabolites, N- nitrohydroxymethylmethylamine and N- nitromethylamine were tested for mutagenicity in histidine auxotrophic Salmonella typhimurium strains in a variety of conditions. N- Nitrodimethylamine was mutagenic only in S. typhimurium TA 100 after pre-incubation with bacteria and a complete metabolizing mixture containing 9000 g liver supernatant and NADPH-regenerating cofactors. N- Nitrohydroxymethylmethylamine and formaldehyde were approximately equally mutagenic without the metabolizing mixture in TA 100 and TA 98, but not in TA 1535. The addition of the 9000 g supernatant of homogenized liver increased the yield of his+ revertants induced by the two compounds. N- Nitromethylamine was not mutagenic with or without the metabolic activation system. The results suggest that formaldehyde is possibly the mutagenically active intermediate formed during in vitro metabolism of N- nitrodimethylamine . Furthermore the participation of formaldehyde as the mutagenic intermediate of other non-alkylating N-nitro and N-nitroso compounds is demonstrated.
Carcinogenesis 1984 Jun
PMID:Formaldehyde as a possible mutagenic metabolite of N-nitrodimethylamine and of other agents which are suggested to yield non-alkylating species in vitro. 637 45

CaCrO4 was shown to induce alkali labile sites in the DNA of Chinese hamster ovary cells by analysis of the lack of linearity in the alkaline elution curves, and by a study of the dependence upon pH in the elution of DNA from filters. The effect of CaCrO4 on these parameters was compared with N-methyl-N-nitrosourea, an agent known to produce alkali labile sites. Based upon the aforementioned parameters HgCl2, formaldehyde and X-rays caused the formation of frank single strand breaks with little or no induction of alkaline labile sites. These findings demonstrate differences in the production of alkali sensitive sites by agents that cause DNA single strand breaks.
Carcinogenesis 1984 Sep
PMID:Analysis of the induction of alkali sensitive sites in the DNA by chromate and other agents that induce single strand breaks. 646 9

Results from animal experiments and studies in human subjects indicated that the amount of nitrosoproline (NPRO) excreted in the 24-h urine, following ingestion of precursors, is an index for the rate of endogenous nitrosation; this method was found to be sensitive, reproducible and could be satisfactorily applied to human subjects in clinical and field studies. N-Nitrosothiazolidine 4-carboxylic acid (NTCA) and its 2-methyl derivative (NMTCA) were also identified in the urine of human subjects. As the respective amino precursors (thiazolidine 4-carboxylic acids) can be formed by reaction of formaldehyde or acetaldehyde with cysteine, measurement of NTCA and NMTCA in urine may provide a further index for endogenous nitrosation in the human body and may also allow monitoring of exposure of human subjects to aldehydes, nitrate and nitrite. The yield of nitroso compounds formed endogenously in the human body was shown to be linked to the intake of precursors, but several inhibitors and catalysts, either as pure substances or occurring in complex mixtures, were shown to modify the nitrosation reaction in vivo. In particular, ingestion of ascorbic acid after nitrate-rich meals was efficient in lowering human exposure to endogenously formed N-nitroso compounds. A dose-response relationship was established for the formation of NPRO in rats in vivo, after concurrent administration of various concentrations of the precursors, L-proline and sodium nitrite. The logarithm of the amount of NPRO formed was found to be proportional to the logarithm of the product of the proline dose and the square of the nitrite dose. On the basis of these results, a kinetic model was formulated allowing the estimation of the daily precursor dose quantity, ([amine][nitrite]2), required to give 50% tumour incidence in rats after two years of feeding. The potential application of this model, for the estimation of carcinogenic risk from endogenously formed N-nitrosamines in humans, is discussed. Our results demonstrate unequivocally the endogenous formation of N-nitroso compounds in the human body, the significance of which in human carcinogenesis remains to be established.
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PMID:Monitoring endogenous nitrosamine formation in man. 654 81

The in vitro reaction between disulfiram (DSF) and N-nitroso[14C]dimethylamine [( 14C]NDMA) was studied. Incubations of DSF with [14C]NDMA were carried out in the presence of rat liver microsomes, control 9000 g (S9) supernatant fraction and phenobarbital-induced S9 fraction. H.p.l.c. analysis and liquid scintillation measurement provided evidence for the formation of methyldiethyldithiocarbamate (MeDDTC) as a product of the reaction between diethyldithiocarbamate (DDTC), the main active metabolite of DSF and the 'methyl-cation' released by NDMA after enzymatic activation. The amount of MeDDTC found here was consistent with the rate of oxidation of NDMA to formaldehyde. Scintillation counting confirmed that other radioactive peaks, not due to MeDDTC, were unrelated to the methylation of L-cysteine by [14C]NDMA.
Carcinogenesis 1984 Feb
PMID:Chemical interaction of disulfiram with nitrosodimethylamine after in vitro enzymatic activation. 669 38

A dose-dependent increase in the transformation rate in Styles' cell transformation assay using BHK-21/cl.13 cells was observed after exposure to formaldehyde and hexamethylenetetramine. The toxic and transforming effect was equal after exposure to 20 micrograms/ml of formaldehyde or 1000 micrograms/ml of hexamethylenetetramine which is slowly hydrolysed in aqueous solution to form ammonia and formaldehyde.
Carcinogenesis 1983
PMID:Formaldehyde and hexamethylenetetramine in Styles' cell transformation assay. 683 18

The rate of hydrolysis to formaldehyde of methylenedimorpholine (MDM), hexamethylenetetramine (HMT) and dinitrosopentamethylenetetramine (DNPT) have been compared with the enzyme-mediated formation of formaldehyde from hexamethylphosphoramide (HMPA). The bio-distribution of [14C]HMPA following nasal instillation in rats has also been studied and compared with that of [14C]methyl methanesulphonate (MMS). These data are used to relate the several carcinogenic/genotoxic properties of the chemicals named above. It is concluded from these data and related considerations that three classes of formaldehyde-generators should be recognized (a) labile agents such as MDM (and formaldehyde) which are likely to be locally active as carcinogens, (b) lipophilic and relatively stable agents such as HMPA which may be both locally active (if bio-accumulated) and systemically active as carcinogens, and (c) agents such as HMT and DNPT, of intermediate stability, which are unlikely to be systemically active and to be of low or zero activity locally.
Carcinogenesis 1982
PMID:Formaldehyde generators: relationship between stability, lipophilicity and carcinogenic potency. 715 Dec 45

The microsomal metabolism of eight methyl alkyl nitrosamines (nitrosotrifluoroethylamine, nitrosomethylpropylamine, nitrosomethylpentylamine, nitrosomethylneopentylamine, nitrosomethylhexylamine, nitrosomethylheptylamine, nitrosomethylcyclohexylamine and nitrosomethylbenzylamine) was studied. All the nitrosamines produced formaldehyde during metabolism but only nitrosotrifluoroethylamine failed to produce the expected second carbonyl product. All the nitrosamines with the exception of nitrosomethylpropylamine exhibited simple Michaelis-Menten kinetics. The latter compound showed two distinct kinetic curves. The chain length of the second alkyl moiety appeared to have a profound influence on the metabolism of the methyl group to formaldehyde.
Carcinogenesis 1982
PMID:The metabolism of a series of methylalkylnitrosamines. 715 Dec 48

The purpose of this investigation was to compare the response of human cell types (bronchial epithelial cells and fibroblasts and skin fibroblasts) to various DNA damaging agents. Repair of DNA single strand breaks (SSB) induced by 5 krads of X-ray was similar for all cell types; approximately 90% of the DNA SSB were rejoined within one hour. During excision repair of DNA damage from u.v.-radiation, the frequencies of DNA SSB as estimated by the alkaline elution technique, were similar in all cell types. Repair replication as measured by BND cellulose chromatography was also similar in epithelial and fibroblastic cells after u.v.-irradiation. Similar levels of SSB were also observed in epithelial and fibroblastic cells after exposure to chemical carcinogens: 7,12-dimethylbenz[a]anthracene; benzo[a]pyrene diol epoxide (BPDE); or N-methyl-N-nitro-N-nitrosoguanidine. Significant repair replication of BPDE-induced DNA damage was detected in both bronchial epithelial and fibroblastic cells, although the level in fibroblasts was approximately 40% of that in epithelial cells. The pulmonary carcinogen asbestos did not damage DNA. DNA-protein crosslinks induced by formaldehyde were rapidly removed in bronchial cells. Further, epithelial and fibroblastic cells, which were incubated with formaldehyde and the polymerase inhibitor combination of cytosine arabinoside and hydroxyurea, accumulated DNA SSB at approximately equal frequencies. These results should provide a useful background for further investigations of the response of human bronchial cells to various DNA damaging agents.
Carcinogenesis 1982
PMID:DNA repair in human bronchial epithelial cells. 715 Dec 52

Utilizing the microsomal fraction isolated from hamster liver we have identified and quantitated some of the alkylation lesions introduced into exogenous DNA as a consequence of the microsomally-mediated decomposition of 14C-labeled dimethylnitrosamine and have established correlations between this DNA alkylation and formaldehyde formation. The yield of radiolabeled formaldehyde was assessed by the formaldemethone-precipitation method and the yields of the major methylated purines present in a mild acid hydrolysate of modified DNA determined using cation exchange high pressure liquid chromatography techniques. We found 7-methylguanine, 3-methyladenine and O(6)-methylguanine in our DNA hydrolysates in the same relative proportions as observed in DNA isolated from similar incubation mixtures containing methylnitrosourea as the methylating compound. The rate of DNA methylation was observed to correlate well with the rate of formaldehyde formation and, even thought the absolute formaldehyde and DNA methylation yields varied in experiments done on different days, the relative yields were found to be consistent. Both processes were NADPH dependent, both were inhibited by carbon monoxide, and both were equally sensitive to chemical agents which appear to interfere with dimethylnitrosamine metabolism in vivo.
Carcinogenesis 1981
PMID:The in vitro methylation of DNA by microsomally-activated dimethylnitrosamine and its correlation with formaldehyde production. 727 16

Hexamethylphosphoramide (HMPA) is an aprotic polar solvent and nasal carcinogen in rats. The metabolism of HMPA to formaldehyde, another nasal carcinogen in rats, was found to be approximately 6 times greater in microsomes from olfactory tissues than from respiratory tissues (isolated from both male and female rats). HMPA was shown to induce formation of DNA-protein crosslinks (DPXLS) in isolated rat nasal epithelial cells. Using a filter binding assay, we demonstrated that microsomal activation is necessary for HMPA-induced crosslink formation between plasmid DNA and calf thymus histones, presumably through metabolic N-demethylation of HMPA and the formation of formaldehyde. Both formaldehyde production and DPXL formation were inhibited by pre-incubation of nasal mucosal extracts with metyrapone, an inhibitor of cytochrome P-450. Significant dose-dependent increases in DPXL formation were observed in respiratory and olfactory epithelial cells exposed to > or = 0.5 and 1 mM HMPA, respectively, for 3 h at 37 degrees C. This resulted in DPXL accumulation at 18-20% higher levels than untreated cells. Increases in DPXL formation in rat nasal epithelial cells cultured with 1 mM HMPA were inhibited by over 70% by co-administration of metyrapone. These data suggest that metabolic liberation of formaldehyde from HMPA is involved in the mechanism of HMPA-induced nasal carcinogenesis. Comparative studies showed formaldehyde to be more potent than HMPA in the induction of DPXL in nasal epithelium. However, induction of tumor formation after two years at 50 ppb HMPA and 6 ppm formaldehyde show the former to be active at several-fold lower concentrations. Therefore, other mechanisms are likely to be involved in HMPA nasal carcinogenesis.
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PMID:DNA-protein crosslink formation in rat nasal epithelial cells by hexamethylphosphoramide and its correlation with formaldehyde production. 762 75


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