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PubMed1981

Suppressive effect of aluminium chloride administration on mouse lung carcinogenesis by dimethylnitrosamine.

Dimethylnitrosamine was administered to mice by ip injection once a week for 3 weeks and a high incidence of lung tumor was found 6 approximately 8 months after the final injection. In experiment I, the incidence of mice with lung tumors was 74% and the average number of nodules per mouse was 15.6 within 6.0 months after the final injection of dimethylnitrosamine. In mice given aluminium pretreatment, these values decreased to 65% and 6.7 (P less than 0.05), respectively. In experiment II, the incidence of mice with lung tumors was 100% and the average number of nodules per mouse was 8.7 within 7.5 months after the final injection of dimethylnitrosamine. In mice given aluminium pretreatment, these values decreased to 79% and 4.6 (P less than 0.05), respectively.

Adenocarcinoma↗
PubMed1994

DNA as a critical target in toxic cell death: enhancement of dimethylnitrosamine cytotoxicity by DNA repair inhibitors.

Our working hypothesis states that DNA damage is a critical step in toxic cell death. The DNA hypothesis was tested in cultured mouse hepatocytes by examining whether inhibitors of DNA repair would increase dimethylnitrosamine toxicity and DNA damage in parallel. Inhibitors were chosen for selectivity toward DNA polymerase alpha (aphidicolin, myricetin), DNA ligase (ethidium bromide), or multiple repair enzymes (ara-C, doxorubicin). Dimethylnitrosamine caused concentration-dependent DNA damage at 6 hr and cell death at 24 hr (35% ALT release vs. 8.8% in control cultured hepatocytes). Each repair inhibitor increased dimethylnitrosamine-induced DNA damage and toxic cell death in parallel. Doxorubicin maximally elevated DNA fragmentation and toxicity (57% ALT release). Repair inhibitors alone failed to damage DNA or cause cell death in this model system. These data support the hypothesis that DNA damage is an early causal event in toxic cell death caused by alkylating hepatotoxicants.

Animals↗
PubMed1996

Temporal cell-type-specific mRNA expression of O6-methylguanine-DNA methyltransferases in liver of rats treated with dimethylnitrosamine.

The intercellular distribution of O6-methylguanine-DNA methyltransferase (MGMT) mRNA expression has been investigated at the individual cell level in the liver of rats treated with dimethylnitrosamine using in situ hybridization. Male BDIV rats were orally administered with a single dose of dimethylnitrosamine (5 or 10 mg/kg) and were killed at 24, 48, and 96 hours after exposure. Constitutive MGMT mRNA expression was found in bile duct cells, vascular endothelial cells, and fibrous cells; however, weak or negative expression was detected in hepatocytes and Kupffer cells. On the other hand, after exposure to dimethylnitrosamine, inducible MGMT mRNA was rapidly expressed in hepatocytes, especially in the centrilobular area at earlier time points, confirming our previous studies in which enzymatic activity has been measured in different purified cell populations obtained by differential centrifugation. Immunohistochemical detection of the O6-methylguanine-DNA adduct formation was demonstrated in a dose-dependent fashion and was mainly found in the centrilobular hepatocytes where high levels of MGMT mRNA were present. These results suggest a correlation between the induction of this repair activity and DNA damage; however, the relationship between MGMT mRNA and enzyme activity remains to be fully established for all cell types.

Administration, Oral↗
PubMed1970

Cellular injury and carcinogenesis. Inhibition of metabolism of dimethylnitrosamine by aminoacetonitrile.

1. Aminoacetonitrile, a lathyrogenic agent known to decrease the hepatotoxic action of dimethylnitrosamine, inhibited the metabolism of this compound by rats in vivo and by rat liver slices in vitro. 2. Methylation of nucleic acids in rat liver and kidney by dimethylnitrosamine in vivo was inhibited by treatment of the animals with aminoacetonitrile. 3. These findings are discussed in relation to the hypothesis that dimethylnitrosamine requires metabolism to exert its hepatotoxic and carcinogenic action.

Animals↗
PubMed1971

The stability of rat liver ribonucleic acid in vivo after methylation with methyl methanesulphonate or dimethylnitrosamine.

1. RNA was isolated from rat liver at selected times after the intraperitoneal injection of either [(14)C]methyl methanesulphonate (50mg/kg) or [(14)C]dimethylnitrosamine (2mg/kg). These doses were chosen to minimize effects due to toxicity. 2. Two methods of extraction and purification of RNA were used and an analysis of the radioactivity present was made by column chromatography of acid hydrolysates of the purified RNA. 3. The extent of methylation of guanine, the principal site of alkylation in rat liver RNA, was determined at times up to 14 days after injection. Although dimethylnitrosamine is a potent liver carcinogen and methyl methanesulphonate is not carcinogenic to rat liver, the rate of disappearance of 7-methylguanine from RNA was similar for both compounds, with a half-life of about 3.5 days. 4. An estimate of the biological half-life of rRNA was made by using [(3)H]orotic acid. A half-life of 5 days was obtained and this was not affected by injecting animals with unlabelled methyl methanesulphonate at the same dosage of 50mg/kg used in the studies of RNA methylation. 5. After administration of labelled orotic acid, reutilization of labelled RNA degradation products probably results in an overestimation of the biological half-life for rRNA. It is suggested that non-toxic doses of methylating agents such as methyl methanesulphonate and dimethylnitrosamine may prove to be a more effective way of accurately estimating the biological turnover of RNA species.

Alkanes↗
PubMed1988

Possible role of certain antioxidant enzymes in dimethylnitrosamine-induced liver carcinogenesis.

An investigation was carried out to establish whether the reduction in catalase, glutathione peroxidase and superoxide dismutase activity, normally observed in liver tumours, is an early event and therefore of pathogenetic importance, or whether it is a late occurrence. Experiments performed on dimethylnitrosamine-treated hepatectomized and non-hepatectomized rats show that the decrease in activity of these enzymes is entirely due to hepatectomy, since the tumour-inducing doses of dimethylnitrosamine failed to provoke variations in the activity of these enzymes, in either normal or regenerating liver.

Animals↗
PubMed1990

Morphological and immunohistochemical characteristics of dimethylnitrosamine-induced malignant mesenchymal renal tumor in F-344 rats.

Mesenchymal renal tumors in F-344 newborn rats were induced by a single dose of dimethylnitrosamine. The induced tumors were successfully transplanted into adult rats under the renal capsule. Neither the primary nor the transplanted neoplasms from various generations of grafts changed their morphological features during the tumor passage, having the same cellularity with high mitotic activity and the tendency to invade the host kidney rapidly. On the basis of lectin histochemistry and immunohistology, the tumor proved to be a mesenchymal neoplasm without any obvious capacity of the proliferating cells to differentiate into any well-known organoid element normally found in mature renal parenchyma. However, the proliferating neoplastic cells were found to have a strong vimentin positivity with desmin expression. Ultrastructurally, myofilaments with attachment bodies characteristic of smooth muscle cells were generally present in various amounts in many tumor cells. In addition, on the basis of the physiological data and on kidney/tumor renin activity obtained, it is interesting to note that the tumor-graft-invaded kidneys retained their enzyme activity, despite the obvious loss of renal tissue including glomeruli. However, the immunohistochemical findings with anti-renin antibody have clearly shown that this is not due to a renin-producing tumor but rather to the surviving (probably) non-neoplastic arterioles retaining the capacity to produce renin. Although these arterioles have mostly been found next to necrotic areas, commonly occurring in dimethylnitrosamine-induced transplantable renal tumors, the question of a possible physiological role of renin in tumor necrosis or in angiogenesis has remained open.

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↗
PubMed1982

Dimethylnitrosamine adducts excreted in rat urine.

Rats were injected with [14C]dimethylnitrosamine and urine was collected up to 5 days after the injection. Urine samples were concentrated and subjected to Sephadex G-10 chromatography. Three peaks of radioactivity (I-III, in the order of elution) were observed for all injection times. The peaks were analysed further by cation exchange and thin-layer chromatography and by phase-separation (pH-determination). The pK-determinations and the chromatographic properties suggested that Sephadex fraction I composed of methylated amino acids, such as N-acetyl-S-methylcysteine, 1-methylhistamine and S-methylcysteine, in addition to radioactive methionine. Sephadex fraction II was suggested to compose of allantoin and of a metabolite of thiazolidine-4-carboxylic acid. The latter compound was a reaction product of formaldehyde and cysteine, indicating activity of the formaldehyde moiety released from dimethylnitrosamine. By gel filtration properties Sephadex fraction III indicated identity as 7-methylguanine. Although the urinary radioactivity accounted for about 9% of the applied dose.

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↗
PubMed1981

A mutagenicity methodology for assessing the formation of N-dimethylnitrosamine in vivo.

The mutagenicity test methodology in vitro has been extensively used during recent years in the identification of potential carcinogenic agents. Mutagenic analyses have been applied to the study of chemical reaction products for the demonstration of the formation of mutagenic agents. Recent studies have indicated that secondary and tertiary amines, when reacted with nitrite in acidic conditions, yield N-nitroso compounds, including the potent carcinogen N-dimethylnitrosamine (NDMA). This finding raises the problem of risk evaluation of several food components of human diets for the presence of potential carcinogenic compounds. By combining a mutagenicity test procedure with yeast cells inoculated into the blood system of mice and incubated in the liver for various times (minutes or hours) we have devised a model methodology which allows the detection of the formation of N-dimethylnitrosamine (NDMA) at a level lower than 1 mg/kg. The methodology has been examined for its use in the study of activators of the nitrosation, such as thiocyanate, and of inhibitors of the nitrosation, such as ascorbic acid and tannic acid. Other food components of the human diet, such as red wine, have also been investigated by this methodology.

Animals↗
PubMed1982

The differential effects of the carcinogen dimethylnitrosamine on isocitrate and 6-phosphogluconate metabolism in single intact cells.

A microspectrofluorimetric study is made of the influence of dimethylnitrosamine on NADP reduction, following sequential microinjections into the same L cell, of two substrates: (1) isocitrate, with activity of isocitrate dehydrogenase both in the extramitochondrial and intramitochondrial compartments, (2) 6-phosphogluconate, with activity of the dehydrogenase in the extramitochondrial compartment. In control L cells a two-step reduction of NAD(P) is obtained followed by relatively slow reoxidation. In the minutes which follow addition of carcinogen, e.g., dimethylnitrosamine, to the cell medium the isocitrate and 6-phosphogluconate-induced transient NADP reoxidation is decreased in magnitude compared to control, while the rate constant of NADPH reoxidation is considerably accelerated, possibly due to requirements at the level of the microsomal metabolizing system. Observation within the first hour of carcinogen addition suggest an interesting system for evaluating the immediate actions of carcinogens at extranuclear sites: i.e., a comparative study of NADP reduction-reoxidation rate constants via injection of substrates for extra- vs. intramitochondrial pathways.

Animals↗
PubMed1992

Quantitative analysis of proliferating sinusoidal cells in dimethylnitrosamine-induced cirrhosis. An immunohistochemical study.

Proliferating lipocytes (fat-storing cells or perisinusoidal stellate cells of the liver) were detected by in vivo incorporation of bromodeoxyuridine (BrdU) in an experimental model of cirrhosis in the rat by dimethylnitrosamine. Lipocytes were identified by sequential double immunohistochemical staining on frozen sections using anti-desmin antibodies as a marker of cytoplasmic intermediate filaments followed by anti-BrdU antibodies to identify S-phase nuclei in animals treated for 7, 14 or 21 days. The number of desmin-positive (lipocytes) and desmin-negative (Kupffer and endothelial cells) sinusoidal cells incorporating BrdU was recorded. The labelling index of lipocytes was calculated as the percentage of BrdU-labelled desmin-positive cells with respect to total number of lipocytes. In control animals, when the total number of lipocytes was 153.9 +/- 11/mm2 (mean +/- 1 S.E.) the number of desmin-positive S-phase sinusoidal cells never exceeded 6.8 +/- 1.2/mm2 with a maximum labelling index of 4.3 +/- 0.5%. At 7 days of treatment, the values were respectively 236 +/- 26.5/mm2, 53.2 +/- 5.9/mm2 and 22.6 +/- 0.5% (p less than 0.001 vs. controls), while, at 21 days they were 272.5 +/- 21.2/mm2, 23.3 +/- 4.0/mm2 and 8.5 +/- 1.1% respectively (p less than 0.01). These results show that hyperplasia of lipocytes represents an early reaction to dimethylnitrosamine-induced liver injury. The local accumulation of lipocytes appears to occur in areas where fibrous septa develop later on.

Animals↗
PubMed1985

In vivo distribution of dimethylnitrosamine metabolites in mouse liver and their binding to micrococcal nuclease sensitive and resistant chromatin.

Mice were injected i.p. with a single dose (5 mg/kg body wt) of [14C]dimethylnitrosamine and killed at time intervals between 15 and 120 min. Isolated nuclei were incubated with micrococcal nuclease and the chromatin separated into a 1100 g pellet P1 and supernatant fraction S1. The incorporation of 14C from [14C]dimethylnitrosamine into chromatin was significantly higher in the P1 than the S1 fraction. The purine bases of the P1 DNA showed a lower methylation than those of the S1 DNA. In contrast, radioactivity of the proteins was higher in the P1 than the S1 fraction. It is concluded that the open structures of the S1 chromatin were preferentially attacked by the hepatotoxin leading to a high 14C-labelling of the DNA relative to that of the proteins.

Animals↗
PubMed1996

Glycoprotein metabolism in dimethylnitrosamine induced hepatic fibrosis in rats.

Glycoproteins play a major role in the pathogenesis of hepatic fibrosis by accumulating in the sinusoids and the space of Disse. In order to obtain more information about the altered metabolism of glycoproteins during the development of human hepatic fibrosis, the carbohydrate moieties of the glycoproteins were monitored in experimentally induced hepatic fibrosis. The liver injury was induced by injecting dimethylnitrosamine intraperitoneally in male albino rats. The injections were given on the first 3 consecutive days of each week over a period of 21 days. Glycoprotein moieties such as total hexose, hexosamine, fucose and sialic acid were estimated in liver, serum and urine samples on days 7, 14 and 21 of the experiment. The results indicated a significant decrease in total hexose and an increase in fucose levels in the liver tissue during dimethylnitrosamine administration. While protein bound hexose in the serum showed a significant decrease, sialic acid levels were notably increased. The other glycoprotein moieties both in liver and serum also showed an increase in the later periods of study, especially on day 21. All glycoprotein moieties exhibited a significant increase in the rate of urinary excretion on the 14th and 21st days, indicating an increased rate of metabolic degradation in the acute phase of hepatic fibrosis. The results suggest that glycoproteins undergo changes in both synthesis and the degradation during hepatic fibrosis. The relative alterations in these processes will play a vital role in determining the progression of hepatic fibrosis.

Animals↗
PubMed1976

DNA damage and repair in intact animals. Single-stranded regions in rat liver DNA following administration of dimethylnitrosamine.

Rat liver DNA was radioactively labelled by administration of [3H]thymidine following partial hepatectomy. Two weeks later, the rats were treated with the carcinogen, dimethylnitrosamine. DNA was isolated and fractionated by elution from benzoylated DEAE-cellulose with NaCl and caffeine solution. The caffeine-eluted fraction was increased by administration of dimethylnitrosamine. This increase was proportional to the dose of carcinogen injected and persisted for at least 24 h after administration of the carcinogen. These data, together with the results of hydroxyapatite chromatography, suggest that the DNA contains short single-stranded sections associated with much longer regions of native DNA.

Animals↗
PubMed1976

Effect of chronic administration of dimethylnitrosamine on the excision of O6-methylguanine from rat liver DNA.

Rats were exposed chronically to unlabelled N,N-dimethylnitrosamine (25 ppm in the drinking water) then given a single dose of N-[3H]methyl-N-nitrosourea (10 mg/kg body weight). The rates of loss of tritium-labeled 7-methylguanine, O6-methylguanine and 3-methyladenine from the liver DNA in control and dimethylnitrosamine-treated rats were found not to be significantly different. Thus, under the conditions used, inhibition of the O6-methylguanine excision repair system does not seem to be a factor in the induction of liver tumours by chronic DMN application.

Adenine↗
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↗