[The role of various pesticides in nitrosamine-induced carcinogenesis].
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Animals↗
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Results for “Methylurea Compounds”
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Induction of mouse lung adenomas by amines or ureas plus nitrite and by N-nitroso compounds: effect of ascorbate, gallic acid, thiocyanate, and caffeine.
Lung adenomas were induced in strain A mice by chronic treatment with N-nitroso compounds (given in drinking water) and with amines or ureas in food plus NaNO2 in drinking water. We studied the effects of varying the concentrations of three N-nitroso compounds and NaNO2 concentration in the morpholine plus NaNO2 and methylurea plus NaNO2 systems. Sodium ascorbate (NaASC) at the highest level tested (11.5 or 23 g/kg food) gave 89-98% inhibition of adenoma induction by the NaNO2 plus piperazine, morpholine, and methylurea systems. In 7 groups, NaASC produced increases of 15-59% in adenoma induction by nitrosomorpholine (NM) and mononitrosopiperazine (MNP), possibly because the mice consumed more of the nitrosamine solution. Adenoma induction by morpholine plus NaNO2 was strongly inhibited by gallic acid, moderately inhibited by caffeine, and unaffected by thiocyanate (all added to the food). Gallic acid inhibited or had no effect on the action of NM and MNP. We discussed the proposal that NaASC (or perhaps gallic acid) be administered with readily nitrosatable drugs.
Adenoma↗
Characterization of BIBS 39 and BIBS 222: two new nonpeptide angiotensin II receptor antagonists.
Two new nonpeptide angiotensin II (AII) receptor antagonists, 4'-[(2-n-butyl-6-cyclohexylaminocarbonylamino-benzimidazole-1-yl)- methyl ] biphenyl-2-carboxylic acid (BIBS 39) and 2-n-butyl-1-[4-(6-carboxy-2,5-dichlorobenzoylamino)-benzyl]-6-N- (methylaminocarbonyl)-n-pentylamino-benzimidazole (BIBS 222) were characterized in radioligand binding assays, and in vitro and in vivo experiments. BIBS 39 displaced [125I] AII from its specific binding sites with a K(i) value of 29 +/- 7 nM for the AII subtype I (AT1) receptor and a K(i) value of 480 +/- 110 nM for the AII subtype 2 (AT2) receptor. BIBS 222 showed a K(i) value of 20 +/- 7 nM for the AT1 subtype and a K(i) value of 730 +/- 170 nM for the AT2 subtype. Thus BIBS 39 was 17 times more selective for the AT1 subtype and BIBS 222 37 times. Both compounds were specific for AII receptors as they did not show high affinity for other receptors. BIBS 39 shifted the AII concentration-contractile response curves in isolated rabbit aorta to the right in a parallel fashion. A pA2 value of 8.14 +/- 0.08 and a slope of 1.06 +/- 0.07 were calculated. BIBS 222 caused nonparallel shifts to the right and reduced the maximal response induced by AII by about 25%. A KB value of 9.01 (+/- 3.22) x 10(-8) M was determined. At 10(-5) M, neither compounds altered the contractile responses to noradrenaline and KCl. In pithed rats, BIBS 39 dose dependently shifted the dose-response curve of AII to the right without affecting the maximal response.(ABSTRACT TRUNCATED AT 250 WORDS)
Angiotensin Receptor Antagonists↗
Eugenol causes oxidant-mediated edema in isolated perfused rabbit lungs.
Eugenol, an extract of cloves, has been associated with pulmonary edema when inhaled from commercially available clove cigarettes. We tested the hypothesis that eugenol directly causes lung edema through oxidant-mediated mechanisms by infusing eugenol (0.1 and 1.0 mM) into isolated rabbit lungs perfused with a cell-free albumin and physiologic salt solution. We observed lung edema (1.0 mM) as demonstrated by increased lung weight gain and wet-to-dry lung weight ratios without alterations in mean pulmonary artery pressure. The oxygen metabolite scavengers catalase (1,000 U/ml) and dimethylthiourea (30 mM) attenuated lung edema. Instillation of dimethylurea, superoxide dismutase, or heat-inactivated catalase did not prevent lung edema formation. We conclude that eugenol causes lung edema in isolated lungs through oxidant-mediated mechanisms in the absence of circulating formed blood elements. Eugenol may be a valuable compound in the laboratory investigation of edemogenic disorders.
Animals↗
In vitro and preliminary in vivo studies of compounds which induce the differentiation of Friend leukemia cells.
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Acetamides↗
In vivo formation of N-nitroso compounds and detection of their mutagenic activity in the host-mediated assay.
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Animals↗
Environmental mutagens that induce the adaptive response to alkylating agents in Escherichia coli.
Many microorganisms exhibit an adaptive response to mutagenic alkylation damage. In Escherichia coli the response is regulated by the inducible Ada protein. A sensitive immunoassay employing two anti-Ada monoclonal antibodies has been developed here to monitor low levels of induction of the Ada protein. This protein was detected in non-induced E. coli which contained an average of two molecules of Ada per cell. The occurrence of the adaptive response in bacteria signals the existence of an ecological niche in which cells are exposed to direct-acting methylating compounds, but the structure and identity of these agents are unknown. Using the immunoassay to search for possible candidates, a number of methylating agents and precursors of such agents have been investigated. Carbamyl phosphate and methylamine yield N-methylurea, which reacts subsequently with nitrite to generate the strong inducer N-methyl-N-nitrosourea. The antibiotic streptozotocin also is a potent inducer of the adaptive response. Moreover, the abundant environmental mutagen methyl chloride acts as an inducer.
Adaptation, Physiological↗
N-mineralization of formaldehyde-releasing N-compounds.
The mineralization of several N-compounds, such as MMU, DMU, and HMT, as well as their respective nitrificide action, have been investigated. It has been proved that the amount of available formaldehyde, as well as its rate of release, are responsible for the specific action of these compounds on the N-mineralization process. Factors affecting the rate of release, namely molecular structure, solubility, and temperature, are discussed as well. Importance of these N-compounds as slow-release N-fertilizers based on a new molecular-microbiological approach is described.
Bacteria↗
Inhibition of chemical Epstein-Barr virus induction by dimethyl sulfoxide and related polar compounds.
Dimethyl sulfoxide and twelve related polar compounds, capable of inducing differentiation of murine erythroleukemia cells, markedly inhibited induction of Epstein-Barr virus antigens in virus producer and nonproducer lymphoblastoid cells exposed to 12-O-tetradecanoylphorbol-13-acetate, n-butyric acid, 5-iodo-2'-deoxyuridine, and a combination of 12-O-tetradecanoylphorbol-13-acetate and n-butyric acid. The concentration at which these compounds caused 90% inhibition of antigen induction corresponded to that optimal for induction of differentiation. At the same concentrations, polar compounds did not affect cell viability or virus induction by superinfection with Epstein-Barr virus recovered from P3HR-1 cells. The inhibitory activity was reversible. Three nonpolar differentiating compounds revealed no inhibitory activity.
Acetamides↗
Individual susceptibility of mice to a mutagen in both germ and somatic cells.
Male Swiss mice received simultaneously, by gavage, 500 mg methylurea/kg body weight and 25 mg sodium nitrite/kg body weight, and in a further experiment 330 mg of methylurea/kg and 17 mg sodium nitrite/kg, for 5 consecutive days. This treatment resulted in a dose-dependent mutagenic effect in both the dominant-lethal and the micro-nucleus tests. Furthermore, in both mammalian tests, some animals were more susceptible to the mutagenic compounds than were others. However, the liver microsomal metabolizing system did not seem to be responsible for this variation of mutagenic induction.
Animals↗
[The pre- and postnatal carcinogenic effect of 3,3-diethyl-1-methyl-1-nitrosourea (DEMNU) in rats following intravenous application].
The pre- and postnatal administration of DEMNU induces a high frequency of tumors when applied via the intravenous route, and the latency periods show a dose dependence (table I). Tumors of the brain, spinal cord and cranial nerves clearly predominate. Furthermore, a large number of neoplasms of kidney, heart and soft tissue was observed (table II). As DEMNU is per se a very stable compound, it is suggested that this agent is metabolized by monooxygenases. 3-Ethyl-1-methyl-1-nitrosourea should be formed as an intermediate product via this pathway, which is relatively stable and might explain the mainly neurotropic carcinogenicity of DEMNU. Species differences in the carcinogenicity of trialkyl-nitrosoureas and the mode of metabolic activation are discussed.
Animals↗
Deuterium isotope effect on the toxicokinetics of monomethylamine in the rat.
The single-dose toxicokinetics of monomethylamine has been characterized in the rat by HPLC assay of serial blood samples. Biphasic first-order elimination was observed following an iv bolus dose of 19 mumol/kg with a terminal half-life of 19.1 +/- 1.3 min (mean +/- SE, N = 4). The apparent steady state volume of distribution, systemic blood clearance, and renal blood clearance were 1.21 +/- 0.09 liter/kg, 53.4 +/- 3.5 ml/min/kg, and 5.72 +/- 0.53 ml/min/kg, respectively. The administration of an intragastric dose permitted the calculation of the systemic bioavailability of monomethylamine as 69 +/- 3%. Duplicate experiments using the structural analogue with deuterium atoms substituted for hydrogens on the methyl group revealed a much slower elimination of the compound, although ultimately, 5 times as much was excreted unchanged in the urine. Isotope effects calculated as the ratios of terminal half-life, systemic blood clearance, and systemic bioavailability were 1.9, 2.2, and 1.8, respectively.
Animals↗
Metabolism of a new herbicide, tebuthiuron (1-[5-(1,1-dimethylethyl)-1,3,4-thiadiazol-2-yl]- 1,3-dimethylurea), in mouse, rat, rabbit, dog, duck, and fish.
Orally dosed tebuthiuron was readily absorbed in mice, rats, rabbits, dogs, and ducks. The compound was extensively metabolized and the metabolites were rapidly excreted in the urine of mice, rats, rabbits, and dogs and in the mixture of urine and feces in ducks. The major metabolites of tebuthiuron were formed by N-demthylation of the substituted urea side chain in each species examined, including fish. Oxidation of the dimethylethyl group occurred in mice, rats, dogs, rabbits, and ducks. The N-demethylation reaction at the 3-position of the urea proceded through an N-hydroxymethyl intermediate. No accumulation of tebuthiuron or its metabolites was observed in the animals, a finding consistent with the low order of toxicity observed in other studies.
Animals↗
Inducers of Friend leukaemic cell differentiation in vitro--effects of in vivo administration.
Studies were conducted of the in vivo therapeutic potential of compounds which induce the differentiation of Friend leukaemia cells (FLC) in vitro. DBA2/J mice were inoculated with Friend leukaemia cells grown in tissue culture and at various times thereafter were treated with either N-methylacetamide, dimethylacetamide, or tetramethylurea. While survival was only occasionally prolonged, in every study these agents significantly inhibited leukaemia cell proliferation in the spleen and to a lesser extent in the marrow. These agents had no effect on the rate of proliferation of FLC growing subcutaneously nor on the proliferation of myeloid leukaemia in RFMS mice. These studies indicate that the administration of inducing agents to mice bearing Friend leukaemia can alter the proliferation characteristics of the leukaemia cells and hence suggest that these agents may have therapeutic potential.
Acetamides↗
Formation of N-(5-nitro-2-thiazolyl)-N'-carboxymethylurea from 5-hydroxyniridazole. Role of aldehyde dehydrogenase in the oxidative metabolism of niridazole.
N-(5-nitro-2-thiazolyl)-N'-carboxymethylurea (NTCU) has been identified as a urinary metabolite of the antischistosomal drug niridazole [1-(5-nitro-2-thiazolyl)-2-imidazolidinone]. When DBA/2J mice were treated with [14C]niridazole, a metabolite comprising 12-14% of the total radioactivity in 24-hr urine samples was resolved by HPLC. The compound was subsequently isolated from pooled urine of niridazole-treated patients. It was identified as NTCU by mass spectrometry, and the deduced structure was confirmed by chemical synthesis. NTCU is unique among known niridazole metabolites, because it lacks an intact imidazolidinone ring. Its structure allows for a ketoenol tautomerism in which the enolate is stabilized by conjugation with the nitrothiazole ring, as evidenced by a pH-dependent 80-nm red shift in the absorption spectrum. We hypothesized that NTCU arises via oxidation of an acyclic aldehyde tautomer of 5-hydroxyniridazole, one of two proximate oxidative niridazole metabolites. Indirect evidence for the aldehyde tautomer included the fact that 5-hydroxyniridazole displayed the same pH-dependent spectral shift as NTCU with a single isobestic point at 388 nm. The proposed precursor-product relationship was confirmed when we found that NTCU formation from 5-hydroxyniridazole was catalyzed by NAD(+)-dependent aldehyde dehydrogenase (EC 1.2.1.3). The activity copurified with benzaldehyde dehydrogenase activity from mouse liver cytosol. Furthermore, benzaldehyde was a competitive inhibitor of 5-hydroxyniridazole dehydrogenase activity. These results demonstrate that 5hydroxyniridazole is not an end product of niridazole metabolism. Because biotransformation of niridazole to its 4- and 5-hydroxy derivatives has been implicated in the drug's carcinogenicity and central nervous system toxicity, NTCU formation appears to represent a detoxication pathway in mammals.
Aldehyde Dehydrogenase↗
'Laterally aggregated' polyacrylamide gels for electrophoresis.
A new method is described for producing highly porous polyacrylamide matrices: polymerization in presence of a preformed hydrophilic polymer. If a standard mixture of monomers (e.g., 5%T, 4%C) is polymerized in presence of, e.g., polyethylene glycol (PEG) 10 kDa, lateral chain aggregation occurs, with formation of large pore sizes. In PEG 10 kDa, the transition from a small- to a large-pore gel is clearly apparent at 0.5% PEG addition and reaches a plateau already at 2.5% PEG. Even with shorter PEG fragments (6.2 and 1 kDa) this transition occurs, but with progressively larger amounts of PEG in solution (up to 25% for the 1 kDa species). Other polymers such as hydroxymethyl cellulose (1000 kDa) and polyvinyl-pyrrolidone (360 kDa and 25 kDa) are also able to elicit this phenomenon. It appears that lateral chain aggregation (before the cross-linking event) is induced via intra-chain hydrogen bonding, since urea and temperature strongly inhibit it, whereas tetramethylurea (an agent quenching hydrophobic interactions) does not hamper it. By scanning electron microscope, it is found that the maximum pore size obtained in a 5%T, 4%C gel in presence of 2.5% PEG 10 kDA is of the order of 0.5 micron, whereas the same 5%T, 4%C control gel would have an average pore diameter of 5 nm. Thus, an increment of pore size of about 2 orders of magnitude is obtained: in these new matrices, a 21000 bp DNA fragment exhibits a much greater migration than in a control gel in which the sample is entrapped at the application site.
Acrylic Resins↗
[The determination of thiazafluron in drinking water].
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Chromatography, Thin Layer↗
Role of the extracellular matrix on the growth and differentiated phenotype of murine colonic adenocarcinoma cells in vitro.
The growth and differentiation characteristics of MAC 15 murine adenocarcinoma cells, derived from routine passage in vivo for growth in vitro on a plastic substrate (MAC15j cells), were compared under conditions in which the cells were seeded onto a substrate of type-I collagen which was either attached to plastic or was released to float free in medium. Cells grown on a plastic substrate consisted of a heterogeneous, largely anaplastic population with a putative enterocytic morphology but with no evidence of junctional complexes or cell polarity typical of an epithelial phenotype. MAC 15j cells from cultures grown on a plastic substrate reestablished a moderate to well-defined degree of differentiation when transplanted back into NMRI mice. When MAC 15j cells were seeded from plastic onto type-I collagen, either attached to plastic or free-floating, tight junctional complexes were formed and the cells began to attain a more recognizable, columnar and polarised epithelial morphology. Cells grown on a type-I collagen gel which was free-floating showed a selective expression of alkaline phosphatase at the apical surfaces of approximately 10% of the cells. This expression was detectable by electron microscope histochemistry but could not be detected biochemically. Treatment of MAC 15j cells grown on a released collagen matrix with tetramethyl-urea (20mM) accelerated the expression of alkaline phosphatase activity at the apical surface as detected by microscopy.
Adenocarcinoma↗