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PubMed1977

Protein bound carboxyl-methyl ester as a precursor of methanol formation during oxidation of dimethylnitrosamine in vitro.

Protein modification with dimethylnitrosamine was studied in vitro in the presence of hamster liver microsomal fraction. Incorporation of radioactive methyl groups from dimethylnitrosamine into the exogenously added protein was dependent on the microsomal mixed function oxidase system. The methylation yielded chemically labile and stable products. The former was completely hydrolyzed by the mild alkaline treatment, pH 7.4, 100 degrees C, for 5 min and the hydrolytic product was identified as methanol indicating that the activated methyl groups from dimethylnitrosamine were incorporated into a protein as a carboxyl-methyl ester. Thus, it is suggested that methanol, recovered as one of the products during the biodegradation of dimethylnitrosamine [8], is derived, at least in part, from protein carboxyl-methyl ester which is unstable under physiological conditions.

Animals↗
PubMed1979

Studies on the distribution and metabolism of 14C-dimethylnitrosamine in foetal and young mice.

In pregnant mice injected with 14C-dimethylnitrosamine, whole-body autoradiography was performed with hemisections at -80 degrees (to prevent evaporation of the volatile dimethylnitrosamine) and with dry tape sections (to localize the non-volatile metabolites). The results indicated that the non-metabolized substance passed to the foetal tissues with a uniform distribution and without formation or accumulation of non-volatile metabolites. Autoradiography in young (1-10 days old) and adult mice showed a high level of metabolites in the liver already 5 min. after the administration of 14C-dimethylnitrosamine. No metabolism of the substance could be detected at in vitro incubations of liver tissue obtained from foetuses on the last day of gestation (14CO2-production and incorporation of radioactivity in acid-insoluble macromolecules were used as metabolic indices). However, in vitro experiments with livers of 1-5 days old mice indicated a rapid increase in enzymatic activity after birth. Studies in vivo showed an increased incorporation of radioactivity in the acid-insoluble macromolecules of the liver and a decreased exhalation of 14CO2 in 10 and 14 days old mice as compared with 21 and 60 days old mice. This indicates a difference in the fate of dimethylnitrosamine in vivo between the young and older mice.

Animals↗
PubMed1985

Toxicokinetic and metabolic study of dimethylnitrosamine and diethylnitrosamine in crayfish Austropotamobius pallipes.

The acute toxicities of dimethylnitrosamine and diethylnitrosamine have been evaluated in adult male crayfish Austropotamobius pallipes; LD50 values are 2250 mg/kg and 230 mg/kg, respectively. Toxicokinetic studies of 14C-dimethylnitrosamine and 14C-diethylnitrosamine in crayfish, administered by i.v. injection, show high concentrations of 14C in abdominal muscle and hepatopancreas. Excretion is greater with dimethylnitrosamine, and retention in the tissues, especially the hepatopancreas, is greater with diethylnitrosamine. Metabolites identified in excreta include monomethylnitrosamine from dimethylnitrosamine, and hydroxyethyl-ethyl-, bishydroxyethyl- and carboxyethyl-ethylnitrosamine from diethylnitrosamine.

Animals↗
PubMedDate not supplied

[On the problem of dimethylnitrosamine formation from tetracycline-derivatives by nitrosation reaction in acidic medium (author's transl)].

The hydrochlorides from tetracycline and six tetracycline derivatives -- 7-dimethylamino-6-des-methyl-6-desoxytetracycline [minocycline], 7-chlorotetracycline [chlorotetracycline], 7-chloro-anhydrotetracycline [anhydrochlorotetracycline, 7-chloro-6-desmethyltetracycline [demethylchlorotetracycline], 5-hydroxytetracycline [oxytetracycline] and 6-desoxy-5-hydroxytetracycline [doxycycline] -- were reacted with different amounts of sodium nitrite at 37 degrees C for two hours in aqueous buffer solutions at pH 2 and 4. Dimethylnitrosamine formation was confirmed by gas-liquid chromatography and by combined gas-liquid chromatography/mass-spectrometry from minocycline, doxycycline, oxytetracycline and anhydrochlorotetracycline. Dimethylnitrosamine formation from minocycline and doxycycline was blocked by ascorbic acid. The catalytic effect of sodium thiocyanate for the dimethylnitrosamine formation from minocycline and nitrite was investigated. The different reactivity of the investigated tetracycline derivatives towards nitrite in acidic solutions is discussed by stereochemical considerations in connection with the formation of hydrogen bridge linkages. This hypothesis was confirmed by dimethylnitrosamine formation from anhydrochlorotetracycline and sodium nitrite at pH 2.

Ascorbic Acid↗
PubMed1979

Increased excision of O6-methylguanine from rat liver DNA after chronic administration of dimethylnitrosamine.

Male BDIV rats were given dimethylnitrosamine (2 mg/kg daily) by stomach tube on weekdays for a total of 9 weeks, the final dose being of 14C-labeled material. Control rats received only the labeled dimethylnitrosamine. Liver DNA was isolated at various times later (from 2 to 12 hr), and normal and alkylated purines were determined after hydrolysis in mild acid by chromatography on Sephadex G-10. The levels (measured as dpm/micronmol of parent base) of 7-methylguanine in the DNA of the pretreated rats were the same as or slightly higher than those of the control animals, and the persistence of this product was similar in both groups. This was also true for 3-methyladenine. In contrast, the initial amount of O6-methylguanine in the liver DNA of the pretreated rats was one-third of the amount found in the control rats, and the rate of loss of this product from DNA was higher in the pretreated animals. These differences were reflected in the alkylation product ratios: the 3-methyladenine:7-methylguanine ratios were closely similar in the two groups of animals at all times, whereas the O6-methylguanine:7-methylguanine ratio was initially 3 times higher in the control animals and fell more slowly. DNA synthesis (as measured by the incorporation of [3H]thymidine) was higher in the liver, kidney, and lung of rats receiving dimethylnitrosamine pretreatment. These findings are discussed with respect to the hepatocarcinogenicity of chronically administered dimethylnitrosamine.

Animals↗
PubMed1978

Alterations in thermal stability of rat liver chromatin and DNA induced in vivo by dimethylnitrosamine and diethylnitrosamine.

A study was made of the effects of administration to rats of dimethylnitrosamine and diethylnitrosamine on the transition temperature (Tm) of sheared chromatin and DNA isolated from the liver. The analysis was made by thermal chromatography on hydroxylapatite with the use of DNA prelabeled with [3H]thymidine and following the elution pattern during the operation of a continuous temperature gradient. With a nonnecrogenic dose of dimethylnitrosamine (10 mg/kg), the alterations in chromatin were maximal at 24 hr and disappeared by 3 days. Greatest differences in elution profiles of chromatin after dimethylnitrosamine treatment were observed in the region above 80 degrees. Administration of the carcinogen caused a lowering of the "melting" curve in this region, the displacement from control position being proportional to the dose. The maximum dose (60 mg/kg) displaced the complete chromatin melting curve up to 5 degrees to the lower side. DNA isolated from this chromatin melted 3 degrees less than that from control rats. However, administration of lower doses of dimethylnitrosamine did not affect the melting profile of DNA. The administration of diethylnitrosamine caused a similar type of change. However, the modification was also seen at 50-60 degrees.

Animals↗
PubMed1983

[Action of F- on liver metabolism of dimethylnitrosamine and benzo(a)pyrene in the rat].

The authors carried out this study according to three parameters (dose, level, age of the rats and way of administration) on the action of fluor study in liver metabolism of dimethylnitrosamine and benzo(a)pyrene. The results showed that, in parallel with the increase of the dose level, at certain concentrations, it occurs generally an induction of dimethylnitrosamine-demethylase and a decrease in the amount of cytochrome P450 either by intraperitoneal injection, by ingestion or by inhalation. On the other hand, fluoride does not affect benzo(a)pyrene metabolism. Moreover, inhalation of FH looks the most suitable for this study. It allows to keep a relatively constant rate of F' in the blood and bring about more important changes in the metabolism of dimethylnitrosamine (30 to 70% induction) and in the amount of cytochrome P450 (10 to 40% decrease), as compared to the controls. The results suggest that, in the conditions of our experiments, fluoride would exert an favourable effect on the carcinogenic power of dimethylnitrosamine without affecting benzo(a)pyrene one.

Animals↗
PubMed1981

Alkylation of intracellular and extracellular DNA by dimethylnitrosamine following activation by isolated rat hepatocytes.

Freshly prepared rat hepatocytes isolated by perfusion with collagenase were able to metabolize microM concentrations of dimethylnitrosamine to a methylating agent. The methylation of hepatocyte DNA in this system was complete within 2 hr, and after this time, the content of O6-methylguanine in the DNA declined, showing that the repair system for this product was active in the isolated hepatocytes. When extracellular calf thymus DNA was added to the incubated hepatocytes, this also became methylated. Methylation of this DNA was not due to cell lysis releasing activating enzymes into the medium, showing that the methylating species formed by the hepatocytes from dimethylnitrosamine is sufficiency stable to pass out of the cell in substantial amounts. These results support the possibility that alkylation of liver cells would not be confined to those cells metabolizing dimethylnitrosamine but could be extended to those cells which are in close proximity to the activating cells. These cells could include nonparenchymal cells which are known to be targets for the carcinogenic action of dimethylnitrosamine.

Alkylating Agents↗
PubMed1980

Methylated purines in human liver DNA after probable dimethylnitrosamine poisoning.

DNA, isolated from two samples of human liver obtained from a suspected dimethylnitrosamine poisoning, contained 1363 to 1373 micromol of 7-methylguanine per mol of guanine and 273 to 317 micromol of O6-methylguanine per mol of guanine. Liver and kidney DNA obtained from unrelated cases contained no detectable methylated purines. From the DNA methylation levels, it is estimated that the dimethylnitrosamine-poisoning victim had been exposed to a dose of 20 mg or more of dimethylnitrosamine per kg of body weight. The results indicate for the first time that humans, like rodents, appear to activate dimethylnitrosamine metabolically to a strong methylating agent, resulting in methylation of liver DNA at both the 7- and O6 positions of guanine.

Adult↗
PubMed1967

A possible mechanism of inhibition of protein synthesis by dimethylnitrosamine.

1. The incorporation of [(14)C]leucine into liver proteins of rats was measured in vivo at various times after treatment of the animals with dimethylnitrosamine and was correlated with the state of the liver ribosomal aggregates. Inhibition of incorporation ran parallel with breakdown of the aggregates. 2. Inhibition of leucine incorporation into protein and breakdown of ribosomal aggregates were not preceded by inhibition of incorporation of [(14)C]orotate into nuclear RNA of the liver. 3. Evidence was obtained of methylation of nuclear RNA in the livers of rats treated with [(14)C]dimethylnitrosamine. 4. Zonal centrifugation analysis of radioactive, nuclear, ribosomal and transfer RNA from livers of rats treated with [(14)C]dimethylnitrosamine revealed labelling of all centrifugal fractions to about the same extent. 5. It is suggested that methylation of messenger RNA might occur in the livers of dimethylnitrosamine-treated rats and the possible relation of this to inhibition of hepatic protein synthesis is discussed.

Animals↗
PubMed1979

Drug-nitrite interactions: species and sex differences in the formation of dimethylnitrosamine and its effects on the hepatic enzyme activities.

Aminopyrine interacted with sodium nitrite in the stomachs of rats and guinea pigs forming dimethylnitrosamine, which affected the hepatic microsomal drug metabolism and certain hepatic enzyme activities. Sex and species differences in changes in the enzyme activities were observed after single or simultaneous administration of aminopyrine and sodium nitrite. A protective effect on dimethylnitrosamine formation with ascorbic acid and alpha-tocopherol was observed. The in vivo formation of dimethylnitrosamine by several antibiotics and an antihistaminic drug with tertiary amino group was also examined.

Aminopyrine↗
PubMed1978

Effect of hypophysectomy on persistence of methylated purines in rat liver deoxyribonucleic acid after administration of dimethylnitrosamine.

The formation of methylated purines in DNA following dimethylnitrosamine administration was studied in control and hypophysectomized rats. When given the same dose of this carcinogen (in mg/kg body weight) the formation of the major product 7-methylguanine and of the minor products 1-, 3- and 7-methyladenine and 3-methylguanine was slightly greater in the livers of hypophysectomized rats than in controls. The rate of loss of these products from the DNA was not affected by hypophysectomy. O6-Methylguanine levels were significantly greater in the hepatic DNA of hypophysectomized rats compared to controls after doses of dimethylnitrosamine ranging from 1 to 20 mg/kg. This difference was due to a slower rate of loss of this purine from the DNA in the hypothysectomized rats. Growth hormone treatment increased the rate of removal of O6-methylguanine in the hypophysectomized rats but did not restore the activity to that found in controls. The possible significance of these results in the induction of tumors by dimethylnitrosamine is discussed.

Adenine↗
PubMed1976

Alkylation of meseenger RNA by dimethylnitrosamine.

Rats were treated with radioactive dimethylnitrosamine or methyl methanesulphonate and the alkylation of various RNA fractions was determined 4 h later. It was found that after administration of dimethylnitrosamine, hepatic messenger RNA (isolated by binding to oligo(dT)-cellulose) and nuclear RNA were alkylated slightly, but significantly less than ribosomal RNA. After treatment with methyl methanesulphonate nuclear RNA was alkylated to a greater extent than either messenger or ribosomal RNA. The implications of these findings with respect to the mechanism by which dimethylnitrosamine inhibits liver protein synthesis are discussed.

Animals↗
PubMed1981

Metabolism of dimethylnitrosamine and subsequent removal of O6-methylguanine from DNA by isolated rat hepatocytes.

Freshly prepared isolated hepatocytes were shown to metabolize dimethylnitrosamine producing an alkylating agent which reacted with cellular DNA giving rise to 7-methylguanine and O6-methylguanine. Alkylation of DNA was prevented by aminoacetonitrile and was proportional to the dimethylnitrosamine concentration over the range of 1--90 microM. Isolated hepatocytes were able to catalyze the removal of O6-methylguanine from their DNA. After formation of this product by reaction with N-methyl-N-nitrosourea or dimethylnitrosamine to give extents of alkylation in the range of 0.1--15.0 mumol O6-methylguanine per mole of guanine in DNA, the loss produced in 3 h incubation was comparable to that seen in vivo from liver DNA alkylated to the same extent. The isolated hepatocytes therefore, provide a useful system in which factors influencing O6-methylguanine persistence in DNA can be studied.

Alkylation↗
PubMed1980

Substrates and inhibitors of hepatic amine oxidase inhibit dimethylnitrosamine-induced mutagenesis in Salmonella typhimurium.

The mutagenic effect of dimethylnitrosamine in Salmonella typhimurium TA100, in the presence of a rat-liver homogenate derived from animals treated with Aroclor 1254, was inhibited by substrates and inhibitors of monoamine oxidase. Substrates of diamine oxidase did not inhibit dimethylnitrosamine mutagenesis and, furthermore, monoamine oxidase inhibitors had no effect on mutagenesis by benzo[a]pyrene or aflatoxin B1. The results suggest that monoamine oxidase participates in the activation of dimethylnitrosamine to a mutagen.

Animals↗
PubMed1976

Suppression of dimethylnitrosamine mutagenicity by nitrososarcosine and other nitrosamines.

Nitrososarcosine, not mutagenic itself in the host-mediated assay using Salmonella typhimurium G46 as indicator organism, lowered the mutant frequency produced by dimethylnitrosamine (DMN). Mutant frequency was significantly depressed when 1.0 g/kg nitrososarcosine was administered by gavage 0.5--2.0 h prior to intramuscular injection of 500 mg/kg DMN. Doses of nitrososarcosine as low as 37.2 mg/kg administered 45 min prior to dimethylnitrosamine treatment produced statistically significant reduction of mutant frequency. Dimethylnitrosamine, diethylnitrosamine and dibutylnitrosamine (500 mg/kg) also partially suppressed the mutant frequency produced by 500 mg/kg DMN when administered 45 min prior to dmn. diethylnitrosamine and dibutylnitrosamine were not found to be mutagenic in this test system.

Animals↗
PubMed1986

Methylation of DNA guanine via the 1-carbon pool in dimethylnitrosamine-treated rats.

Treatment of rats with radioactive methionine and nonradioactive dimethylnitrosamine resulted in the formation of radioactive 7-methylguanine in rat-liver DNA. By comparing the specific activity of administered [14C-Me]-dimethylnitrosamine to the specific activity of isolated 7-methylguanine it was determined that following 20 mg/kg dimethylnitrosamine DNA methylation via the 1-carbon pool may account for up to 30% of the total 7-methylguanine formed.

Animals↗
PubMed1984

The differential effects of dimethylnitrosamine and ethionine on mitochondrial and extramitochondrial dehydrogenases in single intact cells.

In studying the bioenergetics of living cells, the microfluorometric analysis of coenzyme (NAD(P)H) responses to microinjected respiratory and glycolytic substrates enables, in principle, a search for qualitative/quantitative differences in normal versus carcinogen-treated (short-term, long-term) and malignant cells. Responses are compared in L-cells, same adapted to hypertonic media (i.e. L255, L355) and highly malignant rhabdomyosarcoma (CCL 136) cells. The largest responses to respiratory substrate (malate, isocitrate) and the lowest responses to glycolytic substrate (glucose-6-P) are in the L255, 355 cells which exhibit structural rearrangement and dense packing of mitochondria possibly due to high energy requirement for ion pumping. The converse is observed in the CCl 136 where there is no lack of these organelles, but they could be functionally deficient, as suggested by a predominant response to glucose-6-P compared to malate. In the control L-cell, the malate and glucose-6-P responses are relatively well balanced. Upon addition of dimethylnitrosamine to L-cells, there is an initial acceleration in the rate of glucose-6-P-induced NAD(P) reduction (? NADPH requirement for dimethylnitrosamine metabolization), followed by an upsurge of the malate response. In L355 cells, addition of the carcinogens dimethylnitrosamine or ethionine is followed by a strong reductive response to malate, and minimal response to glucose-6-P. The dramatic intensification of the NAD(P)H response to malate in L355 cells pretreated with an ATP trap (ethionine) or an uncoupler (dinitrophenol) strongly points to a requirement for ATP depletion. Weaker enhancement of NAD(P)H response (preferentially after glucose-6-P) is observed in the CCL 136 upon treatment with ethionine. The findings indicate the need for further study on differences in respiratory/glycolytic pathways and efficiency of ATP cycle in malignant cells exhibiting graded differences of structural/functional specialization.

Animals↗