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PubMed1972

Ascorbate-nitrite reaction: possible means of blocking the formation of carcinogenic N-nitroso compounds.

The formation of carcinogenic N-nitroso compounds by the chemical reaction between nitrous acid and oxytetracycline, morpholine, piperazine, N-methylaniline, methylurea, and (in some experiments) dimethylamine was blocked by ascorbic acid. The extent of blocking depended on the compound nitrosated and on the experimental conditions. Urea and ammonium sulfamate were less effective as blocking agents. The possibility of in vivo formation of carcinogenic N-nitroso compounds from drugs could be lessened by the combination of such drugs with the ascorbic acid.

Aniline Compounds↗
PubMed1990

[Derivatives of antineoplastic antibiotics of the daunorubicin series containing methylurea or nitrosomethylurea residues].

Derivatives of antitumour anthracycline antibiotics containing N-methylurea moiety in the carbohydrate ring were obtained by the interaction of methyl isocyanate with daunorubicin, doxorubicin, carminomycin and daunorubicin derivatives, substituted at C-13 or C-14 positions. N-Nitrosation of these compounds yielded modified anthracycline antibiotics containing the N-methyl-N-nitrosourea substituent at C-3' position. Alkaline degradation of these derivatives produced, through corresponding isocyanates cyclic 3'-N,4'-carbonylderivatives. In these anthracycline derivatives with sugar cycles conjugated with oxazoline-2-ones the predominant conformations of sugar ring has changed from 1C4 to 4C1, 2,5B, or B0,3 (shown by 1H NMR spectroscopy). It was demonstrated, both in vitro and in vivo, that introduction of methylurea or cytotoxic methylnitrosourea moieties does not potentiate antimicrobial, cytotoxic or antitumour properties of these compounds.

Animals↗
PubMed1979

[Growth-stimulating action of nitroso compounds on organ cultures of mouse and rat embryonic liver].

Transplacental and direct effects of nitroso-methylurea (NMU) on the organ cultures of the liver of 18-20-day embryos of CBA and C57BL mice and the action of diethylnitroso-amine on the embryo liver cultures of noninbred rats were studied. Nitroso-compounds acclerated explant adaptation, enhanced the culture survival as compared with the normal and induced hyperplastic proliferation of small basophilic cells, whose survival in the experiment and under normal conditions was higher than that in the normal embryonal hepatocytes. The growth-stimulating effect depended on the animal species and strain and on the carcinogen, as weel as on the route of administration.

Animals↗
PubMed1989

Hydroxychavicol: a new anti-nitrosating phenolic compound from betel leaf.

Hydroxychavicol and eugenol are the phenolic compounds isolated from betel leaf (piper betel). The modulation of nitrosation of methylurea by sodium nitrite at pH 3.6 and 30 degrees C was studied. The formation of mutagenic N-nitrosomethylurea was monitored by checking the mutagenicity of reaction mixture in Salmonella typhimurium strain TA100 and TA1535 without S9 mix. Hydroxychavicol and eugenol exhibit dose-dependent suppression of nitrosation in vitro without affecting the survival of the bacteria. Pre- or post-treatment of bacterial cells from S. typhimurium strains TA100 and TA1535 with phenolics did not modify the mutagenicity of nitrosomethylurea. The blocking of hydroxy group(s) in the benzene ring by acetylation abolishes the anti-nitrosating activity of the molecule(s). The nitrosation inhibition by hydroxychavicol is through scavenging of nitrite ions in the media, thus making them non-available for the nitrosation of methylurea.

Areca↗
PubMed2006

Leaching potential of some phenylureas and their main metabolites through laboratory studies.

BACKGROUND, AIMS AND SCOPE: Laboratory studies were conducted with the aim of defining the leaching potential of some phenylureas and their metabolites. A first study was performed for calculating their leaching index (as GUS) on the base of intrinsic properties: persistence (as DT50) and mobility (as Koc) in soil. Another study consisted of aged column leaching experiments whose meaning was to semi-quantify the occurrence of the tested compounds in the leachates, so simulating in field conditions. METHODS: The tested compounds were: diuron, linuron and monolinuron (parents); 3,4-dichloroaniline (DCA), 4-chloroaniline (CLA), 1-(3,4-dichlorophenyl)-3-methylurea (DCPMU), 1-(3,4-dichlorophenyl)urea (DCPU), 1-(4-chlorophenyl)urea (CPU) and monuron, this latter considered both as a metabolite and parent compound. The Koc values of the examined substances were determined by the HPLC screening methods, according to the OECD TG 121. DT50 determinations and aged column leaching experiments were carried out according to SETAC procedures. RESULTS AND DISCUSSION: The examined compounds showed a rather wide range of persistence in soil, with DT50 values less than 2 days for DCA and CLA, close to 8 days for DCPU and CPU and from 16 (diuron) up to 24.8 (DCPMU) days for the others. Their mobility was generally high, based on their Koc values, which ranged from 33 (CPU) to 406 (linuron). The GUS indices indicated that monuron has a clear potential to contaminate groundwater (> 2.8); DCPMU, monolinuron, CPU and diuron are intermediate contaminants (1.8-2.8). Linuron, DCPU, CLA and DCA exhibited a non-leaching behaviour (< 1.8). The aged leaching column experiments showed that parents were found in the leachates at very high percentages respect to the doses applied. The metabolites reached much less percentages, the highest values were observed for monuron from diuron (5.7), CPU (7.2) and DCPMU (8.2%). CONCLUSION: Diuron, Monuron, CPU and DCPMU on the basis of their intrinsic properties, formation from their parents and occurrence in leachates from aged column leaching studies, seem to possess the characteristics of groundwater contaminants. The methodological approach of this study is relatively easy and rapid, hence it can represent a tool for a first screening of compounds such as pesticide metabolites (generally available only in small quantities and for which a field study is not conceivable) or other compounds for which not adequate environmental data are available.

Herbicides↗
PubMed2005

Hydroxylation of the herbicide isoproturon by fungi isolated from agricultural soil.

Several asco-, basidio-, and zygomycetes isolated from an agricultural field were shown to be able to hydroxylate the phenylurea herbicide isoproturon [N-(4-isopropylphenyl)-N',N'-dimethylurea] to N-(4-(2-hydroxy-1-methylethyl)phenyl)-N',N'-dimethylurea and N-(4-(1-hydroxy-1-methylethyl)phenyl)-N',N'-dimethylurea. Bacterial metabolism of isoproturon has previously been shown to proceed by an initial demethylation to N-(4-isopropylphenyl)-N'-methylurea. In soils, however, hydroxylated metabolites have also been detected. In this study we identified fungi as organisms that potentially play a major role in the formation of these hydroxylated metabolites in soils treated with isoproturon. Isolates of Mortierella sp. strain Gr4, Phoma cf. eupyrena Gr61, and Alternaria sp. strain Gr174 hydroxylated isoproturon at the first position of the isopropyl side chain, yielding N-(4-(2-hydroxy-1-methylethyl)phenyl)-N',N'-dimethylurea, while Mucor sp. strain Gr22 hydroxylated the molecule at the second position, yielding N-(4-(1-hydroxy-1-methylethyl)phenyl)-N',N'-dimethylurea. Hydroxylation was the dominant mode of isoproturon transformation in these fungi, although some cultures also produced traces of the N-demethylated metabolite N-(4-isopropylphenyl)-N'-methylurea. A basidiomycete isolate produced a mixture of the two hydroxylated and N-demethylated metabolites at low concentrations. Clonostachys sp. strain Gr141 and putative Tetracladium sp. strain Gr57 did not hydroxylate isoproturon but N demethylated the compound to a minor extent. Mortierella sp. strain Gr4 also produced N-(4-(2-hydroxy-1-methylethyl)phenyl)-N'-methylurea, which is the product resulting from combined N demethylation and hydroxylation.

Agriculture↗
PubMed1977

[Lack of a cancerogenic effect after application of amines and amides together with nitrite in rabbits (author's transl)].

Young rabbits of both sexes received the following nitrosable compounds and sodium nitrite: Group 1:13 animals received 0.1 per cent methylurea in food and 0.1 per cent NaNO2 in drinking water. Two control groups of 6 rabbits were applied NaNO2 or methylurea, respectively. Duration of application 100 days. Group2: 20 animals received 0.2 per cent dimethylbenzylamine in drinking water and 0.15 per cent NaNO2 in food for 100 days. 10 control animals got only 0.2 per cent dimethylbenzylamine. Group 3: 20 rabbits were fed with 0.2 per cent diethylaminohydrochloride and 0.2 per cent NaNO2 added to the food. 10 controls received only 0.2 per cent of the amine. Duration of feeding 63 days.

Amides↗
PubMed2004

Neutrophil-mediated formation of carcinogenic N-nitroso compounds in an in vitro model for intestinal inflammation.

In order to study neutrophil-mediated formation of carcinogenic N-nitroso compounds as a mechanism of inflammation-related colon carcinogenesis, we designed an in vitro model for intestinal inflammation, consisting of a coincubation system with human colon cells (Caco-2 cells) and activated human neutrophils (PMN), as important immunoreactive cells. We investigated whether nitrosamines and nitrosamides could be formed upon addition of dimethylamine, morpholine and methylurea to the coincubations as nitrosatable precursors, which are known to produce carcinogenic N-nitroso compounds. Incubations of pure nitric oxide with dimethylamine and morpholine showed that NO-mediated formation of nitrosodimethylamine and nitrosomorpholine is possible under the incubation conditions. During the coincubations of activated PMN and Caco-2 cells, 0.34 nmol nitrite/10(6) PMN was produced. Dose-dependent formation of NMOR was observed in this PMN/Caco-2 system; addition of 5mM morpholine resulted in a significantly increased NMOR formation of 4.2 nM. However, no detectable NDMA and methylnitrosourea were formed in this coincubation system. These results suggest that activated human neutrophils are able to synthesize carcinogenic N-nitrosamines, e.g. NMOR, which implies a risk of colon carcinogenesis during chronic inflammation. However, the observed relatively low level of nitrosation suggests that also other risk factors are contributing to the association between chronic inflammation and colon cancer risk.

Caco-2 Cells↗
PubMed1981

Quandtitative correlation among DNA damaging potency of six N-nitroso compounds and their potency in inducing tumor growth an bacterial mutations.

Six N-nitroso compounds (N-nitrosodimethylamine, N-nitrosodiethylamine, N-nitrosodi-n-propylamine, N-nitroso-N-methylurea, N-nitrosopyrrolidine, and N-nitrosodi-n-butylamine) were tested in rats for liver DNA damaging activity by the alkaline elution technique. On molar basis their DNA damaging potency was found to decrease in the above order, and to vary over a 28-fold range. The elaboration of homogenous data available from literature showed that the carcinogenic potency of the 6 N-nitroso compounds varied over an 18-fold range, and that their mutagenic potency varied over a 490-fold range. Regression analysis indicated that correlation between carcinogenic and DNA damaging potencies was positive but at a low significance level, while the correlation between carcinogenic and mutagenic potencies was negative.

Animals↗
PubMed2006

Some chemical contaminant of surface sediments at the Baltic Sea coastal region with special emphasis on androgenic and anti-androgenic compounds.

Androgenic and anti-androgenic compounds including p,p'-DDE, Diuron, Linuron, Fenarimol, Vinclozolin, 1-(3,4-dichlorophenyl) urea (DCPU), 1-(3,4-dichlorophenyl)-3-methylurea, (DCPMU), tributyltin (TBT) and triphenyltin (TPT) and their metabolites (DBT, MBT, DPT, MPT) as well as metallic elements (Ni, Cu, Zn, As, Cd, Pb, Co, Tl, Cr, Fe, Mn, Al, K, Mg, Na, Ca, Ba, Ti, Sn), PAHs (16 indicator compounds), DDTs and PCBs have been quantified in top layer (0-10 cm) of up to 37 surface sediment samples collected from several sites in costal zone of the Gulf of Gdańsk, an inland freshwater area of Brdyujście in Poland and the tidal flats of the Norderney Island, Wadden Sea in 2002-2003. These sites differed in the degree of anthropogenic activities, including chemical pollution and related impact on biota. Especially in sediments near shipyards, ship repair facilities, harbours, other industrial activities or close to municipal sewage treatment plant outlets butyltins, PAHs and some metallic elements were found at high concentrations. Diuron, Linuron and DCPMU were detected at a few sites, Fenarimol only once, while Vinclozolin and DCPU were not detected. DDT concentrations in the sediments from the Gdańsk and Gdynia region of the Gulf show a stepwise decrease following the ban for production and use, while diffusion of PCBs at some industrial sites seems to continue. Elevated PAH concentrations in sediments seem to be mainly due to pyrogenic and less to mixed pyrogenic and petrogenic sources, while for a few sites rather petrogenic sources dominated. The reference sites in the Norderney Island, Wadden Sea showed similar or slightly higher loads of DDTs, BTs, PAHs, PCBs and metallic elements when compared to sediments from the least contaminated sites in the coastal Gulf of Gdańsk area, while phenyltins were not detected at both spatially distant European areas.

Androgen Antagonists↗
PubMed1982

The formation and metabolism of N-hydroxymethyl compounds--I. The oxidative N-demethylation of N-dimethyl derivatives of arylamines, aryltriazenes, arylformamidines and arylureas including the herbicide monuron.

The metabolism of the N-methyl moieties of aryldimethylamines and N-methyl compounds of the general formula Aryl-X-N(Me)2, where X is either -N=N-(3-aryl-1, 1-dimethyltriazenes). -NHCO- (N'-aryl-N,N-dimethylureas) or -N=CH- (N'-aryl-N,N-dimethylformamidines) was studied using mouse liver microsomes. Products of microsomal metabolism were reincubated with mouse liver homogenate devoid of microsomes and assayed colourimetrically for formaldehyde. This allows metabolically generated formaldehyde to be distinguished from formaldehyde precursors. Whereas the N-methyl moieties of the aryldimethyltriazenes, formamidines and amines were metabolised to formaldehyde, the aryldimethylureas formed stable formaldehyde precursors upon metabolism. The products of metabolism of one such aryldimethylurea, the herbicide monuron (N'-(4-chlorophenyl)-N, N-dimethylurea) were investigated using a high pressure liquid chromatographic method. Two metabolites were found on incubation of monuron with microsomes, one of which was identified as the N-desmethyl compound by mass spectrometry. The other product showed chromatographic properties similar to 4-chlorophenylurea but resembled the monomethylaryl urea on mass spectral analysis. It is concluded that this metabolite is likely to be N'-(4-chlorophenyl)-N-hydroxymethyl-N-methylurea. A urinary product of conjugative metabolism obtained after the administration of monuron to mice also gave the mass spectrum of the monomethyl compound after deconjugation which suggests that a conjugated N-hydroxymethyl compound may have been formed in vivo.

Amines↗
PubMed1987

DNA damage in the central nervous system of rats after in vivo exposure to chemical carcinogens: correlation with the induction of brain tumors.

The alkaline elution technique has been used to evaluate DNA damage in brain of rats treated with a single equimolar dose of 14 carcinogens of different chemical structure. A clear-cut increase of DNA elution rate, which is considered indicative of DNA fragmentation, was produced by 10 compounds known to induce the development of tumors in the rat central nervous system: N-nitroso-N-methylurea, N-nitroso-N-ethylurea, N-nitroso-N-butylurea, N-nitroso-N-methylurethane, methyl methanesulfonate, ethyl methanesulfonate, dimethyl sulfate, diethyl sulfate, 1,3-propansultone, and procarbazine. Similar amounts of DNA fragmentation were produced by both potent and weak brain carcinogens. In contrast, any significant increase of DNA elution rate was absent in rats treated with N-methyl-N'-nitro-N-nitrosoguanidine, N-nitrosodimethylamine, N-nitrosodiethylamine, and beta-propiolactone, all of which are devoid of carcinogenic activity for the rat central nervous system. These results suggest that the described in vivo brain DNA damage/alkaline elution assay deserves further studies on a wide number of carcinogens and noncarcinogens aimed to establish its possible usefulness for a qualitative preliminary assessment of the ability of a compound to induce neurogenic tumors.

Alkylating Agents↗
PubMed1987

Phenylephrine derivatives as leukotriene D4 antagonists.

Two series of phenylephrine derivatives were prepared and tested as inhibitors of leukotriene D4 (LTD4) induced and ovalbumin-induced bronchospasm in the guinea pig. The most potent compound of the urea series, (R)-N,N-diethyl-N-[2-hydroxy-2-[3-(2-quinolinylmethoxy)phenyl]ethyl]-N- methylurea (3, Wy-47,120), was orally active with ED50's of 56 mg/kg vs. LTD4 and 55 mg/kg vs. ovalbumin. When tested as an antagonist of LTD4-induced contraction of isolated guinea pig tracheal strips, 3 was a competitive inhibitor with a p kappa B value of 5.22. In the second series, (R)-3-methyl-5-[3-(2-quinolinylmethoxy)phenyl]-2-oxazolidinone (26, Wy-47,674) had oral ED50's of 36 mg/kg against LTD4 and 95 mg/kg against ovalbumin. Compound 26 selectively antagonized contractile responses of guinea pig trachea evoked by LTD4 (p kappa B = 6.09). In the cat coronary artery, 3 dilated the preparation and blocked the coronary constrictor effect of LTD4. Compound 3 (0.13 mg/kg, iv) also preserved myocardial integrity in rats 48 h after coronary artery ligation. When tested in the rat alcohol-induced gastric lesion model, 3 and 26 manifested a dose-dependent mucosal protection against ethanol.

Animals↗