PubMed Health⌕ Search

SEARCH · PubMed Health

Results for “Dimethylnitrosamine”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources
PubMed1976

Effects of cytochrome p-448 and p-450 inducers on microsomal dimethylnitrosamine demethylase activity and the capacity of isolated microsomes to activate dimethylnitrosamine to a mutagen.

The relationship between microsomal dimethylnitrosamine (DMN) demethylase activity and the capacity of isolated hepatic microsomes to activate DMN to a mutagen was examined using microsomes from C57 and DBA/2 mice which had been exposed to three different types of microsomal enzyme inducers: phenobarbital, which induces cytochrome P-450, 3-methylcholanthrene, which induces cytochrome P-448, and the polychlorinated biphenyl, Aroclor 1254 which appears to induce both types of cytochromes. DNM induced mutagenesis was assayed by a Salmonella auxotroph reversion test. With the C57 mice all three inducers increased both the activity of microsomal DMN demethylase and the capacity of the microsomes to activate DMN mutagenicity. In each case, however, the increase in mutagenicity was disproportionately greater than the increase in DMN demethylase activity. This was particularly evident with microsomes prepared from Aroclor induced mice. Microsomes from 3-methylcholanthrene treated DBA/2 mice were not induced for DMN demethylase or the activation of DMN mutagenicity. In addition the capacity of Aroclor to function as an inducer was relatively poor in this strain. Both DMN demethylation and mutagenesis were inhibited by the addition of either SKF 525-A or benzo (a)pyrene to the reaction mixtures. Thus microsomal activation of DMN to a mutagen and DMN demethylase appear to involve both cytochromes P-450 and P-448.

Animals↗
PubMed1978

Histological conformity of implantation tumors produced by kidney cell lines derived from dimethylnitrosamine-treated rats, with dimethylnitrosamine-induced renal mesenchymal tumors.

The histology of five implantation tumors induced in rats by the deposition of cultured cell lines derived from dimethylnitrosamine (DMN)-treated rats is described and compared with the morphology of the predominant kidney neoplasm induced in vivo by a single high dose of DMN. The cell lines leading to growth upon implantation were long-established, continuously growing cultures obtained either from a DMN-induced renal mesenchymal tumor or from rats treated shortly before with a carcinogenic dose of DMN. The latter cultures had expressed morphological transformation at subcultures 5 or 6. All of the implantation tumors were of mesenchymal type, comprising variously a range of cell forms including fibroblast-like spindle cells, smooth muscle fibers, and "giant" cells, which resembled common aspects of the parent mesenchymal tumors induced in the rat kidney by DMN. Deposition of cells intrarenally illustrated the survival of remnants of preexisting nephrons as epithelial profiles scattered through the proliferating malignant tissue, a feature most characteristic of the parent tumor. The results confirmed the malignant nature of the various cell lines tested, in keeping with their altered behavior in vitro, and they were consistent also with the premise that the in vivo-in vitro system is selecting cells in culture that represent the same target population from which the renal mesenchymal tumors are derived in vivo.

Animals↗
PubMed1978

Formation and subsequent removal of O6-methylguanine from deoxyribonucleic acid in rat liver and kidney after small doses of dimethylnitrosamine.

1. The amounts of 7-methylguanine and O(6)-methylguanine present in the DNA of liver and kidney of rats 4h and 24h after administration of low doses of dimethylnitrosamine were measured. 2. O(6)-Methylguanine was rapidly removed from liver DNA so that less than 15% of the expected amount (on the basis of 7-methylguanine found) was present within 4h after doses of 0.25mg/kg body wt. or less. Within 24h of administration of dimethylnitrosamine at doses of 1mg/kg or below, more than 85% of the expected amount of O(6)-methylguanine was removed. Removal was most efficient (defined in terms of the percentage of the O(6)-methylguanine formed that was subsequently lost within 24h) after doses of 0.25-0.5mg/kg body wt. At doses greater or less than this the removal was less efficient, even though the absolute amount of O(6)-methylguanine lost during 24h increased with the dose of dimethylnitrosamine over the entire range of doses from 0.001 to 20mg/kg body wt. 3. Alkylation of kidney DNA after intraperitoneal injections of 1-50mug of dimethylnitrosamine/kg body wt. occurred at about one-tenth the extent of alkylation of liver DNA. Removal of O(6)-methylguanine from the DNA also took place in the kidney, but was slower than in the liver. 4. After oral administration of these doses of dimethylnitrosamine, the alkylation of kidney DNA was much less than after intraperitoneal administration and represented only 1-2% of that found in the liver. 5. Alkylation of liver and kidney DNA was readily detectable when measured 24h after the final injection in rats that received daily injections of 1mug of [(3)H]dimethylnitrosamine/kg for 2 or 3 weeks. After 3 weeks, O(6)-methylguanine contents in the liver DNA were about 1% of the 7-methylguanine contents. The amount of 7-methylguanine in the liver DNA was 10 times that in the kidney DNA, but liver O(6)-methylguanine contents were only twice those in the kidney. 6. Extracts able to catalyse the removal of O(6)-methylguanine from alkylated DNA in vitro were isolated from liver and kidney. These extracts did not lead to the loss of 7-methylguanine from DNA. 7. The possible relevance of the formation and removal of O(6)-methylguanine in DNA to the risk of tumour induction by exposure to low concentrations of dimethylnitrosamine is discussed.

Alkylation↗
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↗
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↗
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↗
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↗
PubMed1979

Evidence for several demethylase enzymes in the oxidation of dimethylnitrosamine and phenylmethylnitrosamine by rat liver fractions.

The steady state kinetics and isotope effects were examined for demethylation of dimethylnitrosamine and phenylmethylnitrosamine, as well as their deuterated analogs, using the S-9 fraction, the microsomal pellet, and postmicrosomal supernatant from rat livers. The isotope effect (ratio of maximal rates for the deuterated and light substrates) using the S-9 from Long-Evans rat livers was found to be 1.82 for dimethylnitrosamine and 5.38 for phenylmethylnitrosamine. Phenobarbital was shown to induce dimethylnitrosamine demethylase activity in the microsomal pellet of both Long-Evans and Sprague-Dawley rats but to repress this activity in the postmicrosomal supernatant in the Long-Evans rats, while markedly increasing it in the Sprague-Dawley rats. It was also found that there was nitrosamine demethylase activity in the so-called "pH 5 enzymes" and in the supernatant from that preparation. The latter activity shows substantially different characteristics from that found in the other fractions.

Animals↗
PubMed1979

Methylation of DNAase-digestible DNA and of RNA in chromatin from rats treated with dimethylnitrosamine.

After injecting rats with di[14C]methylnitrosamine we have prepared liver chromatin and have examined firstly, the methylation level of the DNAase I-degradable fraction of the DNA and secondly, the level of methylation and the stability of methylated sites in chromatin RNA. Our results show that the level of 7-methylguanine in the degradable DNA is about 1.3 times that of whole DNA; therefore in the 20% or so of the DNA which is undegradable by DNAase I, the level must be very low or zero. Experiments using chromatin from rats injected with unlabelled dimethylnitrosamine plus [3H]thymidine show that the specific activity is similar in the DNAase I degradable and undegradable fractions, suggesting that there is no preferential repair in the latter region. In chromatin RNA, the level of 7-methylguanine is higher than that of whole DNA and decreases fairly rapidly within 30 h after dimethylnitrosamine treatment. Our results indicate that this decrease is due to some type of excision or repair process rather than to normal turnover.

Animals↗
PubMed1979

Mutagenicity and metabolism of dimethylnitrosamine and benzo[alpha]pyrene in tissue homogenates from inbred Syrian hamsters treated with phenobarbital, 3-methylcholanthrene or polychlorinated biphenyls.

There are significant differences between mice and hamsters in polycyclic hydrocarbon and nitrosamine metabolism. Homogenates of liver, lung and intestinal mucosa from 6 strains of Syrian golden hamster were compared for their ability to metabolize benzo[alpha]pyrene (BP) and dimethylnitrosamine (DMN) to mutagens. Females of strains MHA/SSLak, LSH/SlLak, CB/SsLak, PD4/Lak LHC/Lak and Lak:LVG (SYR) were either untreated or received phenobarbital (PB), 3-methylcholanthrene (MC) or polychlorinated biphenyls (AR) to induce drug-metabolizing enzymes. Salmonella typhimurium TA92 and TA98 were used as indicators of the formation of mutagans. Dimethylnitrosamine demethylase (DMND) was assayed using 1 mM DMN as substrate. Aryl hydrocarbon hydroxylase (AHH) was measured using benzo[alpha]pyrene as substrate. MC does not induced AHH activity in hamster liver, but is an excellent inducer of enzymes converting BP to mutagens. This lack of correlation between increased AHH activity and increased metabolism of BP to mutagen in liver is in marked contrast to correlations seen in mice. MC induces AHH in hamster lung and intestinal mucosa. AR induces AHH in liver, lung and intestinal mucosa. Activity of DMND in liver is not affected by treatment of hamsters with BP or AR, but is repressed approx. 30% by treatment with MC. Activity of DMND and conversion of DMN to mutagen are correlated (r = 0.59) in hamster liver. Microsomes of hamster liver are more effective than those from mouse in converting DMN to mutagen, despite similar DMND activities in livers from the two species.

Animals↗
PubMed1978

Dimethylnitrosamine-induced structural damage to DNA results from repair of O6-methylguanine rather than repair of 7-methylguanine.

DNA isolated from the livers of rats treated with a non-necrotizing dose of [14C]dimethylnitrosamine was fractionated by chromatography of benzoylated-DEAE-cellulose. The preparations of native DNA and DNA containing single stranded regions were then hydrolysed and amounts of methylated guanine determined. Four hours after dimethylnitrosamine treatment there was no difference in the levels of 7-methylguanine and O6-methylguanine in the 2 DNA fractions. By 24 h, although there was no difference in the amount of 7-methylguanine between the DNA fractions, there was a 10-fold difference in the level of O6-methylguanine. The elimination of O6-methylguanine from the fraction of DNA containing single stranded regions is discussed in terms of differing repair processes initiated by 7-methylguanine and O6-methylguanine.

Animals↗
PubMed1976

Inhibition of rat liver RNA polymerases by action of the methylating agents dimethylnitrosamine in vivo and methyl methanesulfonate in vitro.

Dimethylnitrosamine maximally inhibits rat liver nuclear RNA synthesis by 50% at a dose of 40 mg/kg of body weight. The inhibition develops during the first 4 hr and persists through the 12th hr. All parenchymal cells of the lever lobule seem to be affected. The decreased RNA synthesis can be accounted for entirely by an inhibition of the RNA polymerase activities quantitatively solubilized and partially purified. A similar inhibition of the polymerase activities was demonstrated in the intact nuclei by inactivating the endogenous template with actinomycin D and assaying the polymerases with an added exogenous template, poly(deoxy-adenylate-deoxythymidylate). Chromatin was prepared by two methods differing in the extent to which they remove the endogenous polymerase activity. Each preparation was transcribed with either added Escherichia coli or partially purified rat liver nucleoplasmic RNA polymerase. With either polymerase or chromatin preparation, no inhibition of the template activity of liver nuclear chromatin isolated from the DMN-treated animals was detected. A similar mechanism of inhibition of RNA synthesis was produced by the action of the methylating agent methyl methanesulfonate on whole nuclei in vitro. The dose-dependent inhibition of RNA synthesis could be accounted for by an inhibition of the RNA polymerase activities quantitatively solubilized and partially purified from the affected nuclei. Chromatin prepared from the methyl methanesulfonate-treated nuclei had a normal template capacity with either E. coli or rat liver nucleoplasmic RNA polymerase. No preferential methylation of the RNA polymerases by [14C]methyl methanesulfonate could be demonstrated. It is concluded that the action of the two methylating agents on RNA metabolism is similar and that the inhibition of liver nuclear RNA synthesis results from inactivation of the RNA polymerases. At the same time, dimethylnitrosamine and methyl methanesulfonate leave the chromatin template intact, at least quantitatively, for the synthesis of RNA. The implications of such an effect on RNA synthesis are discussed.

Animals↗