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PubMed2003

Synthesis and in vitro calcium antagonist activity of 4-aryl-7,7-dimethyl/1,7,7-trimethyl-1,2,3,4,5,6,7,8-octahydroquinazoline-2,5-dione derivatives.

In this study, a series of 4-aryl-7,7-dimethyl and 1,7,7-trimethyl-1,2,3,4,5,6,7,8-octahydroquinazoline-2,5-diones (1-25) were synthesized by condensing urea or N-methylurea with 5,5-dimethyl-1,3-cyclohexanedione and appropriate aromatic aldehydes according to the Biginelli reaction. The structures of the compounds were confirmed by spectral data and elementary analysis. The calcium antagonist activity of the compounds was tested in vitro on isolated rat ileum and lamb carotid artery. Compounds 16 and 19 were the most active derivatives on isolated rat ileum compared with the standard nicardipine. On isolated aortic strips of lamb the calcium antagonist activity of compound 16 (maximum relaxant effect: 38.83+/-5.84%) was found as high as that of nicardipine (maximum relaxant effect: 35.50+/-4.16%) used as a reference drug.

Animals↗
PubMedDate not supplied

Mutagenesis by N-nitroso compounds: relationships to DNA adducts, DNA repair, and mutational efficiencies.

The relationships between DNA alkylation, DNA repair and mutagenesis by N-nitroso compounds in Salmonella were examined. DNA adducts formed by treatment of the bacteria with N-nitroso compounds were monitored. Critical to the study was establishing which adducts led to mutations. Two methods were employed. In one, correlations in the dose-responses for adducts and mutagenesis were sought. For instance O6-methyl- and -ethyl-guanine, in contrast to other adducts, exhibited thresholds in their accumulation in Salmonella DNA, and mutagenesis at GC base pairs also exhibited the same threshold, suggesting a dependence of mutagenesis on the O6-alkylguanines. In the second method, mutagenesis induced by different mutagens with overlapping adduct spectra was compared. For example, EMS and ENU generate similar ratios of adenine adducts, but only ENU produces thymine adducts, and only ENU induced AT-GC and AT-CG base changes. These observations suggested that ethylthymines led to these mutations. Furthermore, it was found that these mutations were largely dependent on the presence of the plasmid, pKM101, indicating that error-prone repair activity contributes importantly in their processing to mutations. When DNA adducts by N-nitrosopyrrolidine were examined it was found that only one major adduct was detected in an excision-repair-deficient strain, and that this adduct was not present in a repair-proficient strain. Mutagenesis was also greatly reduced in the proficient strain, suggesting that mutagenesis was dependent on this adduct. From the relationships between premutagenic adduct levels and mutagenesis it was possible to calculate estimated values for the mutational efficiencies for several adducts. This calculation assumed an average distribution of adducts and mutations and required knowledge of the target size and the types of mutations that could lead to phenotypic changes. For the unrepaired O6-methyl- and -ethyl-guanines, and the O-ethylthymines the mutational efficiencies were high (ca. 30-70%), but for the N-nitrosopyrrolidine adduct it was low (ca. 1%). Initial studies were carried out on the mutational specificities of two higher homologue N-nitroso compounds (the N-nitroso-N-propyl- and N-butyl-nitroguanidines) in uvrB/pKM101 strains. This class of nitroso compounds is known to form similar DNA adducts as ENU. Their specificities were similar to that of N-nitroso-N-ethylurea at a high dose except the fraction of mutations at AT base pairs was reduced. The fraction of GC-CG transversions was although low, increased. The mutational specificities of N-nitroso-N-methylurea and N-nitrosopyrrolidine were significantly different from the specificity of E

Alkylation↗
PubMed1985

Formation of DNA-damaging nitroso compounds by interaction of drugs with nitrite. A preliminary screening for detecting potentially hazardous drugs.

Fifty-seven theoretically nitrosatable widely used drugs that are commonly administered orally have been screened to determine the formation of nitroso compounds by drug-nitrite interaction and to evaluate the genotoxicity of their nitrosation products against Chinese hamster ovary (CHO) cells, measured as DNA-damaging potency by the alkaline elution technique. The drug (0.1 mmol) was reacted with NaNO2 (0.4 mmol) at pH 3-3.5 for 1 h. Nitroso compounds were present in varying yield in the nitrosation mixture of 47 drugs. Twenty-two drugs formed direct-acting nitroso compounds capable of producing DNA fragmentation, i.e., a statistically significant (p less than 0.01) increase in the elution rate of CHO cell DNA. On a molar basis, their DNA-damaging potency varied over a 570-fold range, with 12 exhibiting greater potency than that of N-nitroso-N-methylurea.

Animals↗
PubMed2006

Effects of temperature and water content on degradation of isoproturon in three soil profiles.

The phenylurea herbicide isoproturon, 3-(4-isopropylphenyl)-1,1-dimethylurea (IPU), is widely used to control pre- and post-emergence of grass and broad-leaved weeds in cereal crops. Its degradation in soils is a key process for assessing its leaching risk to groundwater resources. The degradation properties of various samples from surface and subsurface soil (down to 1m depth) of a heterogeneous agricultural field were studied using (14)C-IPU. Laboratory incubations were carried out at 22 and 10 degrees C and at water contents 90% and 50% of the estimated water holding capacity (eWHC) corresponding to water potentials between -56 kPa and -660 MPa. Degradation was found to be more sensitive to water content variations than to temperature variations in the ranges that we used. For surface layers, at 10 and 22 degrees C, the degradation half-life increased by a factor 10 and 15, respectively, when water content decreased from 90% to 50% eWHC. Under optimal degradation conditions (i.e. 22 degrees C and 90% eWHC), 3-(4-isopropylphenyl)-1-methylurea (MDIPU) was the main metabolite in surface samples. At subsurface depths, IPU half-lives were larger than 100 d, IPU was the main compound after 92 d of incubation and the main metabolite was an unidentified polar metabolite. These results suggest a metabolic pathway involving hydroxylations for subsurface materials. IPU degradation was largely affected by water availability in both surface and subsurface horizons. Clay content seemed to play a major role in degradation processes in subsurface soil by determining through sorption IPU availability in soil solution and/or by limiting water availability for microorganisms.

Biodegradation, Environmental↗
PubMedDate not supplied

Mutagenesis by N-nitroso compounds in Salmonella typhimurium TA102 and TA104: evidence for premutagenic adenine or thymine DNA adducts.

Mutagenesis induced by the N-nitroso compounds: N-nitrosomethylurea, N-nitrosoethylurea, N-nitrosodi-n-propylamine and N-nitrosopyrrolidine was measured in Salmonella typhimurium TA100, TA102 and TA104. TA100 detects damage mainly at G-C base pairs while TA102 and TA104 can detect damage at A-T base pairs. In general all strains were similarly sensitive, except that TA104 was much less sensitive to high doses of N-nitroso-N-methylurea. In TA104 a significant percentage of the revertants induced by all agents except NMU resulted from point mutations at A-T base pairs, indicating that adenine or thymine DNA adducts are important premutagenic adducts formed by certain N-nitroso compounds.

Adenine↗
PubMed2006

Fate of diuron and linuron in a field lysimeter experiment.

The environmental fate of herbicides can be studied at different levels: in the lab with disturbed or undisturbed soil columns or in the field with suction cup lysimeters or soil enclosure lysimeters. A field lysimeter experiment with 10 soil enclosures was performed to evaluate the mass balance in different environmental compartments of the phenylurea herbicides diuron [3-(3,4-diclorophenyl)-1,1-dimethyl-urea] and linuron [3-(3,4-dichlorophenyl)-1-methoxy-1-methylurea]. After application on the agricultural soil, the herbicides were searched for in soil, pore water, and air samples. Soil and water samples were collected at different depths of the soil profile and analyzed to determine residual concentrations of both the parent compounds and of their main transformation products, to verify their persistence and their leaching capacity. Air volatilization was calculated using the theoretical profile shape method. The herbicides were detected only in the surface layer (0-10 cm) of soil. In this layer, diuron was reduced to 50% of its initial concentration at the end of the experiment, while linuron was still 70% present after 245 d. The main metabolites detected were DCPMU [3-(3,4-dichlorophenyl)-1-methylurea] and DCA (3,4-dichloroaniline). In soil pore water, diuron and linuron were detected at depths of 20 and 40 cm, although in very low concentrations. Therefore the leaching of these herbicides was quite low in this experiment. Moreover, volatilization losses were inconsequential. The calculated total mass balance showed a high persistence of linuron and diuron in the soil, a low mobility in soil pore water (less than 0.5% in leachate water), and a negligible volatilization effect. The application of the Pesticide Leaching Model (PELMO) showed similar low mobility of the chemicals in soil and water, but overestimated their volatilization and their degradation to the metabolite DCPMU. In conclusion, the use of soil enclosure lysimeters proved to be a good experimental design for studying mobility and transport processes of herbicides in field conditions.

Diuron↗
PubMed2005

Genistein enhances N-nitrosomethylurea-induced rat mammary tumorigenesis.

Genistein is of great interest for its implications as an anticancer compound. We compared the effects of daily subcutaneous injections of 1mg/kg BW of genistein and vehicle (2% DMSO in peanut oil) for 20 weeks on N-nitroso-N-methylurea (NMU)-induced tumorigenesis in adult female rats. Genistein significantly increased tumor cross-sectional area and tumor multiplicity but not the tumor incidence and latency period when compared with the vehicle treated group. The serum E(2) levels of genistein treated group were significantly higher than those of the vehicle treated group at 1 and 2 months after treatment which is the time when most of the rats developed tumors. There were no significant differences in the length of the estrous cycle, food consumption and weights of body, livers, uteri and ovaries between the two groups. Our data shows that supplementation of genistein at a dosage comparable to the isoflavone consumption in humans did not affect the reproductive system but resulted in enhancement of NMU-induced tumorigenesis in adult female rats. Thus, the supplementation of soy isoflavone in premenopausal women may potentially potentiate the risk of breast cancer.

Animals↗
PubMed1989

Carcinogenesis in rats by nitrosodialkylureas containing methyl and ethyl groups given by gavage and in drinking water.

The carcinogenic effects in male and female F344 rats of four nitrosodialkylureas containing methyl or ethyl groups have been compared by two modes of administration, gavage in oil solution or dissolved in drinking water. Weekly doses of 20 and 40 mumol were given to each rat by either route and treatment lasted usually 30 wk, resulting in a total dose per rat of 0.6 or 1.2 mmol. Nitrosodimethylurea and nitroso-1-methyl-3-ethylurea gave rise primarily to tumors of the nervous system, whereas nitrosodiethylurea and nitroso-1-ethyl-3-methylurea gave rise to tumors of the mammary gland, lung, intestinal tract, nervous system, and testicular mesotheliomas. The effect of nitrosodimethylurea was weaker than that of the other three compounds, as measured by rate of mortality with tumors. Drinking water treatment was less effective than treatment by gavage, by the same criterion. The tumorigenic effects paralleled those of the corresponding monoalkylnitrosourea, suggesting the presence in the target organs of receptors for which ethylnitrosoureas or methylnitrosoureas, respectively, have affinity.

Animals↗