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PubMedDate not supplied

[Effect of low temperatures on the functional state of the membranes of the hepatic endoplasmic reticulum].

Oxidation of fluorescent substrates--NADPH and 4-dimethylamine chalcone (DMC) by microsomes from liver endoplasmic reticulum was studied after freezing and thawing of these cells organelles. Slow freezing to -25 degrees or quick freezing to -196 degrees did not affect distinctly the rate of NADPH oxidation after thawing, but oxidation of DMC by microsomes was decreased in both cases. Freezing and subsequent thawing of microsomes impaired apparently the terminal sites of electron transfer and/or the systems of hydroxylation, including cytochrome P-450. Slow freezing to -25 degrees impaired microsomes more markedly than quick freezing to -196 degrees.

Animals↗
PubMed1975

Degradation of dimethylnitrosoamine catalysed by physical and chemical agents.

Decomposition of dimethylnitrosoamine (DMNA) by chemical and physical agents was further investigated. Both photoirradiation with sunlight or ultraviolet ray and reductive reactions under acid conditions (likely occurring in the stomach) led to the formation of formaldehyde, formic acid, and N-methydrazine, in addition to denitrosated compounds such as methylamine, dimethylamine, and N-methylhydroxylamine. N-Methylhydrazine was the only compound which was not detected by photoirradiation under neutral conditions. The agreement between physiochemical and metabolic degradation products and the possible biological meaning are discussed together with the problem of environmental contamination by the nitroso compound.

Dimethylnitrosamine↗
PubMedDate not supplied

Multiple-endpoint mutagenesis with Chinese hamster ovary (CHO) cells: evaluation with eight carcinogenic and non-carcinogenic compounds.

Previously, we have shown that Chinese hamster ovary (CHO) cells are useful for quantifying chemical-induced gene mutations. We have defined the conditions of a Multiplex CHO System which permits determination of mutagen-induced chromosome aberration, and sister chromatid exchange (SCE) in addition to cytotoxicity and gene mutation in the same treated culture. This allows us to extend the spectrum of quantitative mutagenesis to include clastogenic endpoints. In the present study, we used four carcinogenic/noncarcinogenic pairs to validate the relative utility and sensitivity of each endpoint, and to study the interrelationship of these four distinct biological effects. These compounds include the direct-acting carcinogens N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), ICR 170 and their noncarcinogenic analogue N-methyl-N'-nitroguanidine (MNG) and ICR 170-OH, and the procarcinogens benzo[a]pyrene (B[a]P) and dimethylnitrosamine (DMN) and their noncarcinogenic analogues pyrene and dimethylamine (DMA) respectively. A rat liver homogenate preparation (S9) was used to assay for the biological activities of procarcinogens. Under our experimental conditions, we observed that carcinogens DMN, B[a]P, MNNG and ICR 170, but not their noncarcinogenic counterparts, showed all four biological effects. Our studies with these chemicals showed that cytotoxicity does not necessarily correlate with any of the genetic endpoints. On a molar basis, noncarcinogens, pyrene and ICR 170-OH show similar toxicity to carcinogens B[a]P and ICR 170, respectively. The other two non-carcinogenic analogues, DMA and MNG, exhibit minimal toxicity at concentrations 10-1,000 times higher than cytotoxic concentrations of the corresponding carcinogens, DMN and MNNG. In general, gene mutation and SCE are more sensitive than chromosome aberration assay. The gene mutation assay is more specific than SCE and chromosome aberration assays since none of the noncarcinogens exhibit a detectable response in the gene mutational assay. ICR 170 and MNNG are much more active than B[a]P and DMN as ranked on a molar basis. These results indicate that the Multiplex CHO System is capable of discriminating divergent structural classes of carcinogenic and noncarcinogenic compounds, such as the eight chemicals chosen for our study.

Animals↗
PubMed1986

Induction of rat liver O6-alkylguanine-DNA alkyltransferase following whole body X-irradiation.

The promutagenic DNA lesion O6-alkylguanine can be enzymically removed from cellular DNA by an O6-alkylguanine-DNA alkyltransferase (O6-AT) which transfers the alkyl group from the O6-position of guanine to a cysteine residue contained within its sequence. We report that whole body X-irradiation induces the O6-AT activity in the liver of adult Wistar rats. In vivo repair activity was assessed by radiochromatographic determination of the persistence of O6-methylguanine in hepatic DNA of irradiated rats following a single i.p. injection of N-nitroso-[14C]dimethylamine (2 mg/kg). In addition, the O6-alkylguanine repair capacity was assayed in vitro by incubation of extracts from whole liver, hepatocytes, or hepatic cell nuclei with 3H-methylated DNA and high performance liquid chromatography analysis of this DNA substrate. We found that whole body X-irradiation increased in a dose-dependent manner the O6-AT activity over a range of 100-800 R. The repair induction was first detectable 12 h after X-ray exposure, reached a maximum level at 72 h, and declined to control values within 12 days. Deoxythymidine incorporation into hepatic DNA was significantly reduced during the initial 72 h following application of 500 R. In a split dose irradiation schedule with daily doses of 15 R, a delayed enzyme induction occurred after a 30-day treatment period. Pretreatment of rats with the translational inhibitor cycloheximide completely suppressed the O6-AT stimulation. This indicates that the induction of hepatic O6-alkylguanine repair is due to de novo synthesis of alkyltransferase molecules.

Animals↗
PubMed1987

The ferret as a model for endogenous synthesis and metabolism of N-nitrosamines.

We have begun to evaluate the ferret as a model for studying gastric nitrosation and nitrosamine metabolism. Jugular cannulation allows convenient dosing and sampling of blood, and this technique has been used to study clearance of N-nitrosodimethylamine (NDMA) after intravenous, intraperitoneal and intragastric administration. NDMA metabolism can be inhibited by 4-methylpyrazole for up to 24 h; the accumulation of endogenously-synthesized NDMA can therefore be observed in animals following pretreatment with this compound. We have studied endogenous NDMA synthesis in animals dosed with dimethylamine and nitrite and in animals to which no NDMA precursors were administered.

Animals↗
PubMed1987

Vascular changes and liver tumours induced in mink by high levels of nitrite in feed.

Two groups of female mink were fed a diet supplemented with 30-50 mg/kg bw sodium nitrite for up to six years. The first group also received dimethylamine hydrochloride. Seven male offspring from litters born in the first year were fed the same diet for nine months but showed no pathomorphological change. After three years on trial, female mink developed occlusive changes in some branches of the efferent hepatic veins, and 21% of the mink in group 1 and 31% in group 2 developed liver haemangioendotheliomas or precancerous liver changes. The pathomorphological changes were identical to those seen in animals exposed to N-nitrosodimethylamine (NDMA). This result indicates in-vivo formation of NDMA as a result of the high nitrite in the diet. However, NDMA was not measured in the blood of the nitrite-exposed mink.

Animal Feed↗
PubMed1987

Possible underestimation of nitrosatable amine levels in artificial saliva extracts of children's rubber pacifiers and baby-bottle teats.

Children's pacifiers and baby-bottle nipples from various countries were analysed for their content of N-nitrosamines and nitrosatable amines. Using a method involving extraction with artificial saliva, several nitrosamines including N-nitrosodi-n-butylamine (NDBA), N-nitrosodiethylamine (NDEA), N-nitrosodimethylamine (NDMA) and N-nitrosomorpholine (NMOR) were detected in addition to the three nitrosatable amines dibutylamine (DBA), diethylamine (DEA) and dimethylamine (DMA). Upon nitrosation in artificial saliva, these amines produced not only the related N-nitrosamines but also relatively high levels of the corresponding nitramines--N-nitrodibutylamine (NTDBA), N-nitrodiethylamine (NTDEA) and N-nitrodimethylamine (NTDMA). Thus, both N-nitramines and N-nitrosamines should be measured after nitrosation; otherwise, the method probably underestimates the quantities of nitrosatable amines present in artificial saliva extracts. Whether N-nitramines, some of which have been shown to be both mutagenic and carcinogenic, are formed in the saliva of babies exposed to these products remains to be confirmed.

Cooking and Eating Utensils↗
PubMed1986

[Abnormal effect of nitrosation inhibitors in human gastric juice].

The paper discusses the effect of vitamins C and E and Plantaglucide on nitroso compounds yield in the course of nitrosation of amines in human gastric juice. The study group included 56 subjects. The above drugs capable of inhibiting in vitro nitrosation produced an anomalous effect in gastric juice of some subjects, i.e. potentiated nitroso compounds yield in nitrosation of amines by sodium nitrite. The said action of vitamins C and E was apparent in dimethylamine and amidopyrine nitrosation but it was not in morpholine nitrosation. Sharply increased levels in nitroso compounds were observed in some mice fed precursors of nitroso compounds in combination with vitamin C and Plantaglucide. These data point to an anomalous effect of the drugs on the body.

Animals↗
PubMed1987

An investigation of the relationship between the hepatotoxicity and the metabolism of N-alkylformamides.

The hepatotoxicity and metabolism of the following close analogs of the hepatotoxic antitumor agent N-methylformamide (NMF) were investigated in CBA/CA mice: N-ethylformamide (NEF), dimethylformamide (DMF), formamide and N-methylacetamide (NMA). Apart from NMF only NEF was potently hepatotoxic as measured by the elevation of plasma activities of the enzymes sorbitol dehydrogenase and alanine and aspartate aminotransferases 24 hr after drug administration. In freeze-dried urine samples of mice which had received NEF or NMF, but not in the case of DMF, formamide or NMA, thioesters were detected by thin-layer chromatography. Evidence based on high-pressure liquid chromatography analysis and 400 MHz 1H-NMR and mass spectrometry suggests that the thioester metabolite of NEF is S-(N-ethylcarbamoyl)-N-acetylcysteine. It has been shown previously that NMF is metabolized to S-(N-methylcarbamoyl)-N-acetylcysteine. NEF also underwent extensive metabolism to ethylamine; similarly NMF was biotransformed to methylamine. In contrast, the urine of mice which had received DMF contained only very small amounts of dimethylamine and methylamine could not be detected as a metabolite of NMA. Instead, the major metabolite of NMA was identified by 400 MHz 1H-NMR spectrometry as N-(hydroxymethyl)acetamide. DMF is known to undergo extensive metabolism to its N-hydroxymethyl derivative. The results suggest that two metabolic pathways of N-alkylformamides can be distinguished: Hydroxylation at the alpha-carbon of the N-alkyl group and oxidation of the formyl moiety. The former pathway presumably constitutes a detoxification route, and the latter may well be associated with hepatotoxicity, and affords a glutathione conjugate, excreted in the urine as a mercapturate.

Acetamides↗
PubMed1979

Accelerating effect of ascorbic acid on N-nitrosamine formation and nitrosation by oxyhyponitrite.

The reaction of nitrite ion with ascorbic acid and its effect on the rate of nitrosation of secondary amines have been investigated by differential pulse polarography in aqueous acidic solution. Ascorbic acid shows nonuniform behavior: it accelerates the nitrosation of N-methylaniline between pH 1.00 and 1.95, allows the nitrosation of diphenylamine and iminodiacetonitrile, but inhibits the nitrosation of secondary amines, such as dimethylamine, diethylamine, proline, hydroxyproline, N-methylaminoacetonitrile, N-methylaminopropionitrile, and sarcosine. The nitrosating agent generated by the reaction between ascorbic acid and nitrite ion appears to be oxyhyponitrite ion (N2O3-2).

Ascorbic Acid↗
PubMed1983

Chemical cross-linking studies of the light-harvesting pigment-protein complex B800-850 of Rhodopseudomonas capsulata.

The spatial relationship of the three polypeptides contained in the B800-850 light-harvesting complex of Rhodopseudomonas capsulata has been studied with chemical cross-linking of crude membrane preparations of the phototrophic negative mutant strain Y5. Samples were cross-linked with the cleavable reagent dithiobis (succinimidyl propionate) (1.1 nm chain length) and analyzed by two-dimensional sodium dodecyl sulfate polyacrylamide gel electrophoresis. Membranes labelled with 14C-amino acids were used to determine the compositional stoichiometry of cross-linked products. It was found that the two polypeptides with an apparent Mr of 8000 and 10 000, respectively, that are associated with the pigments bacteriochlorophyll a and carotenoid form homooligomers as well as heterooligomers. The data support the idea that these polypeptides are closely arranged in clusters probably containing at least four of each species. The third subunit with an Mr of 14 000, which is not associated with pigments, was found to be most susceptible to cross-linking and formed homooligomers but no heterooligomers with the other two subunits, and is thus likely to be loosely attached to these clusters. Comparative studies with the phototrophic positive wild type strain indicated that the results found with the phototrophic negative mutant strain Y5 reflect the organization of the B800-850 complex in the membrane of Rhodopseudomonas capsulata. Studies with the isolated B800-850 complex revealed that the sterical arrangement of the three constituent polypeptides in dodecyl dimethylamine-N-oxide containing solutions must be very similar to that in the membrane.

Bacterial Proteins↗
PubMed1984

Comparison of mutagenicities of N-nitrosamines on Salmonella typhimurium TA100 and Escherichia coli WP2 uvrA/pKM101 using rat and hamster liver s9.

The mutagenicities of twelve N-nitrosamines were tested on Salmonella typhimurium TA100 and Escherichia coli WP2 uvrA/pKM101 in the presence of rat liver S9 or hamster liver S9 by "preincubation" and "pour-plate" assays. The following eleven N-nitrosamines were mutagenic: N-nitroso-N-dimethylamine; N-nitroso-N-diethylamine; N-nitroso-N-di-n-propylamine; N-nitroso-N-di-n-butylamine; N-nitroso-N-methyl-n- amylamine ; N-nitroso-piperidine; N-nitrosomorpholine; N-nitroso-N-methyl-piperazine; N-nitroso-N-methyl-benzylamine; N-nitroso-N-methyl- phenylamine and N-nitroso-N-phenyl-benzylamine. N-Nitroso-N-diphenylamine was not mutagenic. E. coli WP2 uvrA/pKM101 was more sensitive than S. typhimurium TA100 to the mutagenic actions of N-nitroso-dialkyl amines, N-nitroso- aklyl -aryl amines and N-nitroso- diaryl amines, but S. typhimurium TA100 was more sensitive to those of N-nitroso-cyclic amines. Hamster liver S9 was better than rat liver S9 for metabolic activation of N-nitrosamines, and the preincubation step enhanced the mutagenicities of N-nitrosamines.

Animals↗
PubMed1984

Genotoxic risk of passive smoking.

More than 60 chemical components are identified in cigarette smoke which have shown to be carcinogenic. The presence of these chemicals is established in mainstream smoke. However, many of them also appear in sidestream smoke resulting in pollution of indoor air, as is shown by the presence of mutagenic substances. Some rather potent carcinogens like N-nitroso-dimethylamine and benzo(a)pyrene have been established in the air of smoke filled rooms. Only a few studies describe internal exposure of passive smokers. Deposition of sidestream smoke in the human respiratory tract has been established for passive smokers. On the other hand, it was shown that inhalation of air contaminated with sidestream smoke results in an increase in the urinary excretion of products mutagenic in the Salmonella/microsome assay. Three epidemiological studies showed an increased risk of lung cancer for non-smoking wives having smoking husbands. Since it is generally acknowledged that most of the genotoxic carcinogens can be detected by in vitro mutagenicity tests, mutagenicity in urine of passive smokers can be considered as an indication of exposure to carcinogens. This observation suggests that there is a causality in the association between increased cancer risk and passive smoking as was found in three epidemiological studies. It is generally accepted that genotoxic chemicals exert their effects in direct proportion to the level of exposure, which means that for these agents no safe thresholds can be established. Several studies clearly show the presence of genotoxic substances in indoor air as a consequence of smoking. Therefore, the outcome of the epidemiological studies is not surprising. As long as half of the human population persists in smoking, the problems of involuntary inhalation of genotoxic substances will continue for the other half. Strategies to control the environmental cancer problem can only be successful if the health hazards of passive smoking are taken seriously.

Air↗
PubMed1984

Nitrosamine carcinogenesis in 5120 rodents: chronic administration of sixteen different concentrations of NDEA, NDMA, NPYR and NPIP in the water of 4440 inbred rats, with parallel studies on NDEA alone of the effect of age of starting (3, 6 or 20 weeks) and of species (rats, mice or hamsters).

A Weibull analysis is presented of the dose and time relationships for the effects on 4 080 inbred rats of chronic ingestion in the drinking water of 16 different doses of N-nitroso-dimethylamine (NDMA) and of N-nitrosodiethylamine (NDEA). The sites chiefly affected were the liver (by both agents) and the oesophagus (by NDEA only). Since the experiment continued into extreme old age, effects became clearly measurable even at a dose of only 0.01 mg/kg per day, which is an order of magnitude lower than previously achieved. (After only two years of treatment, however, the 'TD50' doses needed to halve the proportion of tumourless survivors would have been about 0.06 mg/kg per day of NDEA and about 0.12 mg/kg per day of NDMA.) The general pattern of response was that the log probability of remaining tumourless was given by the product of two terms, the first (the 'Weibull b-value') depending on the dose-rate but not on the duration of exposure, and the second depending not on dose at all but on (approximately the seventh power of) duration. For oesophageal tumours, the 'Weibull b-value' was approximately proportional to the cube of the dose-rate of NDEA (males 21 d3, females 11 d3, where d = dose-rate in mg/kg adult body weight/day, and the background incidence was unmeasurably low. For liver tumours induced by NDEA, the b-value was approximately proportional to the fourth power of dose-rate + 0.04 mg/kg per day (males, 19 (d + 0.04)4; females, 32 (d + 0.04)4), although the relationships were slightly different for the different subsites of liver tumour. This one formula implies both approximate linearity at low doses and an approximately cubic relationship within the higher range of doses that was studied. For liver tumours induced by NDMA, the Weibull b-value was approximately proportional to the sixth power of dose rate + 0.1 mg/kg per day (males, 37 (d + 0.1)6; females, 51 (d + 0.1)6), again with variation between liver subsites, and again implying approximate linearity at low doses. The difference between the latter two relationships may represent differences in the induction of particular DNA repair enzymes by NDMA and NDEA, or in the effects of those enzymes on methylated and on ethylated DNA. These formulae should, of course, be trusted only in the range of doses from which they were derived, and particularly not for those above it.(ABSTRACT TRUNCATED AT 400 WORDS)

Age Factors↗
PubMed1983

Evidence for generation of the precarcinogen nitrosodimethylamine in the small intestine in chronic renal failure.

We have previously reported raised concentrations of dimethylamine and also bacterial overgrowth in the small intestine in CRF. Evidence for in vivo NDMA formation in the same site in CRF is now presented. Gastroduodenal intubation was performed in 9 healthy volunteers and 7 patients with advanced chronic renal failure. Blood, gastric, and duodenal aspirates were analyzed for NDMA. NDMA levels in control and CRF patients for blood were normal, but for gastric aspirate they were 67 +/- 13 and 312 +/- 68 (P less than 0.001) and for duodenal aspirate they were 70 +/- 21 and 319 +/- 47 (P less than 0.001), respectively. The results of bacterial cultures confirmed small intestinal bacterial overgrowth. We thus demonstrated statistically significant differences between NDMA concentrations in the control subjects and patients for both gastric and duodenal aspirates. This suggests that there is increased intestinal generation of NDMA in uremia. The presence of this precarcinogen may be linked with the reported increase in the incidence of cancer in CRF.

Bacteria↗
PubMed1978

Antagonism of the pulmonary vasoconstrictor response to prostaglandin F2alpha by N-dimethylamino substitution of prostaglandin F2alpha.

Efforts to develop an in vivo prostaglandin (PG) antagonist have met with limited success. In this study, N-dimethylamino analogs of PGF2alpha which have proven to be effective in vitro prostaglandin antagonists, were tested for antagonism to the PGF2alpha and arachidonic acid (AA) responses in the canine lung lobe preparation. PGF2alpha (1 microgram/kg) and AA (100 microgram/kg) increased lobar arterial pressure by 54 and 83%, respectively. Infusion of analogs did not change lobar arterial pressure. N-dimethylamine PGF2alpha (0.8-3.2 microgram/ml) antagonized the PGF2alpha response by 66 to 79%. N-dimethylamide PGF2alpha (1.6-8.0 microgram/ml) produced a dose-dependent antagonism (24-75%) with an IC50 value of 3.8 microgram/ml. Neither analog significantly attenuated the pulmonary response to AA. Thus, these N-dimethylamino analogs of PGF2alpha exhibit a potency which is superior to previous in vivo prostaglandin antagonists. In addition, they have effectively differentiated the pulmonary vascular responses of AA and PGF2alpha.

Animals↗
PubMed1984

Synthesis of polar head group homologs of all-trans-cyclopentano-phosphatidylcholine, phosphatidyl-N,N-dimethylethanolamine, and phosphatidylethanolamine.

The polar head group region of a conformationally restricted analog of phosphatidic acid (diacylglycero-phosphate) has been systematically modified to give analogs of phosphatidylcholine, phosphatidylethanolamine, and phosphatidyl-N,N-dimethylethanolamine. These analogs differ from their natural counterpart in both the backbone region and in the polar head region, respectively, as follows: the diacylglyceryl moiety has been replaced by an all-trans diacylcyclopentane-1,2,3-triol moiety and the phosphorus-nitrogen separation has been increased incrementally from two to nine methylene units. The synthesis of these homologous series involved phosphorylation of (1,3/2)-2,3-dipalmitoylcyclopentane-1,2,3-triol with each of a series of homologous bromoalkylphosphoric acid dichlorides, which were themselves obtained by phosphorus oxychloride treatment of the homologous bromoalkanols. The resulting bromoalkyl esters of 2,3-dipalmitoylcyclopentane-1,2,3-triol-1-phosphoric acid were reacted with trimethylamine, dimethylamine, or ammonia to give the cyclopentano-phosphatidylcholines, cyclopentano-N,N-dimethylethanolamines, and cyclopentano-phosphatidylethanolamine, respectively. All the compounds were obtained as stable microcrystalline solids. The yields of cyclopentano-phosphatidylethanolamines and of cyclopentano-N,N-dimethylethanolamines were reduced by the formation of compounds which analyzed as monoacyl (lyso) derivatives.

Chemical Phenomena↗
PubMed1978

[Hydrolysis of the amidine analogs of penicillins].

The products of the hydrolytic degradation of 6-beta-(hexahydro-IH-azepenyl-1)methylenamino) penicillanic acid, 6-beta-(N,N-dimethylformamidino-N1)-penicillanic acid and 6-beta-(morpholinyl-1)methylenamino penicillanic acid were identified with the method of thin-layer chromatography and paper electrophoresis in neutral, acid and alkaline solutions and in the presence of penicillinase. The data of the study showed that acid hydrolysis of the amidine analogues of penicillins resulted in cleavage of the beta-lactame cycle and formation of the respective penicillanic acids. In the alkaline medium the secondary amine (hexamethylenimine, dimethylamine, morpholine) was cleaved from the antibiotic side chain and the resulting N-formyl-6-aminopenicillanic acid was further cleaved up to peniciec acid. The beta-lactame cycle of the antibiotics was cleaved under the effect of penicillinase and the resulting penicilloinic acids degraded into peniciec acid, N-formylpeniciec acid and secondary amines. In the nutral solution the antibiotics were transformed into N-formyl-6-aminopenicillanic acid and penicilloinic acids at the first stage of the hydrolysis followed by their further degradation with formation of N-formylpeniciec acid, peniciec acid and secondary amines.

Amidines↗