Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Diethylnitrosamine”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the 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
PubMed1986

Enhancing effect of co-administration of polychlorinated biphenyls and diethylnitrosamine on enzyme-altered islands induced by diethylnitrosamine in rat liver.

The effect of co-administration of diethylnitrosamine (DEN) and Clophen A 50, a commercial mixture of polychlorinated biphenyls (PCB), on pre-neoplastic enzyme-altered islands in livers of female Sprague-Dawley rats was studied. The islands were identified by the loss of adenosine-5'-triphosphatase (ATPase), emergence of gamma-glutamyltranspeptidase (GGTase) and glycogen storage after fasting. DEN was given p.o. (0.4 or 4 mg/kg body wt respectively) twice a week for 11 consecutive weeks. Clophen A 50 (1 or 5 mg/kg body wt respectively) was given alternatively three times a week for 11 weeks. Four groups of rats each received either DEN or PCBs in the respective doses. Control animals were treated with the vehicle or remained untreated. All animals were killed at week 12. In rats treated with 4 mg DEN/kg body wt approximately 80 ATPase-deficient islands/cm2 were observed. Additional treatment with Clophen A 50 enhanced the island number 3-fold. Treatment with 0.4 mg/kg body wt DEN induced 17 islands/cm2. Additional application of Clophen A 50 enhanced the island number approximately 3-fold. The total island area was enhanced to the same extent in both groups. The island incidence in PCB-treated rats and controls was below 1/cm2 with all markers tested. The results indicate that PCBs may exhibit a co-carcinogenic activity.

Adenosine Triphosphatases↗
PubMed1986

DNA ethylation in hamster tissues during subchronic diethylnitrosamine administration and in the hamster trachea after acute diethylnitrosamine administration.

Formation of O6-ethylguanine (O6EG) in trachea DNA was measured 12 h after acute i.p. administration of 50, 100 and 200 mg diethylnitrosamine (DEN)/kg body wt to Syrian golden hamsters. Purine bases were fractionated by h.p.l.c., and ethylated guanines were quantified optically by fluorescence spectrophotometry. Significant levels of this promutagenic base were found after the various single doses of DEN. O6EG in trachea DNA was also measured at various times up to 48 h after an acute i.p. dose of 200 mg DEN/kg body wt. The maximum level of O6EG was detected 12 h after DEN treatment. A rapid decrease in O6EG concentration was seen in trachea DNA between 12 and 24 h, but only a negligible decrease was detected from 24 to 48 h post-treatment. The formation and accumulation of O6EG in trachea, liver, lung and kidney DNA were determined in hamsters treated subchronically with DEN, 20 mg/kg body wt, s.c. twice weekly up to 8 weeks. O6EG accumulated to significant levels in trachea and liver DNA. 7-Ethylguanine did not accumulate in the DNA of any of the organs studied during subchronic DEN exposure. The formation and persistence of O6EG in trachea DNA of DEN-treated hamsters correlated with the sensitivity of this tissue to the carcinogenic action of DEN.

Alkylation↗
PubMed1992

Diethylnitrosamine-induced increase in gamma-glutamyltranspeptidase in rat liver: its association with thyroid hormone deficiency and its reversal by tri-iodothyronine.

1. The nodular phase of hepatic premalignancy was induced in male Fischer 344 rats by the administration of diethylnitrosamine, 200 mg/kg i.p., followed by promotion utilizing the Solt-Farber promoting regime. 2. Relative to the situation in normal non-treated control rats: the activity of gamma-glutamyltranspeptidase was found to be increased 9.42-fold in homogenate and 7.33-fold in plasma membrane fractions prepared from the livers of saline-injected control rats; and 81.37-fold in homogenates and 91.92-fold in plasma membranes prepared from the livers of diethylnitrosamine-injected rats; plasma levels of total T3 and total T4 were found to be decreased 42.06 and 47.45% in saline-injected control rats and 88.7 and 83.2% in diethylnitrosamine-injected rats, respectively. 3. An early pre-nodular phase of hepatic premalignancy was produced in young immature and mature adult male Fischer 344 rats by the administration of diethylnitrosamine, 75 mg/kg, without subsequent application of the promotion regime. 4. Relative to the situation in control rats: the activity of gamma-glutamyltranspeptidase was found to be increased in liver homogenates prepared from diethylnitrosamine-treated rats, 1.62-fold in young immature rats 1.20-fold in mature adult rats; plasma levels of total T3 were found to be reduced in diethylnitrosamine-treated rats, 28% in young immature rats 9% in mature adult rats. 5. Treatment of diethylnitrosamine-injected young immature male Fischer 344 rats at the prenodular phase of hepatic premalignancy with tri-iodothyronine at 0.005 micrograms/kg s.c. daily for 7 days reversed the diethylnitrosamine-induced increase in liver homogenate gamma-glutamyltranspeptidase activity and the decrease in plasma total T3, restoring these parameters to normal levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1992

Dietary glucarate-mediated inhibition of initiation of diethylnitrosamine-induced hepatocarcinogenesis.

Previously, it has been reported that calcium glucarate is a potent inhibitor of chemical carcinogenesis, including phenobarbital-promoted diethylnitrosamine-initiated hepatic toxicity expressed as altered hepatic foci in rats. The purpose of the present study was to determine whether calcium glucarate could inhibit the immediate and delayed appearance of altered hepatic foci when fed to rats during the initiation phase of diethylnitrosamine-induced hepatocarcinogenesis. The effects of dietary mode of administration of calcium glucarate on the initiation phase of hepatocarcinogenesis were also examined. Since diethylnitrosamine is not known to undergo glucuronidation and calcium glucarate has been shown to enhance clearance of circulating estrogens, an indirect mechanism of action of calcium glucarate was also evaluated by pretreating rats with an anti-estrogen, tamoxifen, prior to partial hepatectomy and administration of diethylnitrosamine. Calcium glucarate significantly inhibited both the early and delayed appearance of altered hepatic foci and exerted maximal inhibition when administered by gavage prior to diethylnitrosamine. Maximal inhibition was obtained when calcium glucarate was provided continuously in the diet of animals up to 5 and 7 months. Pretreatment of animals with tamoxifen before partial hepatectomy and diethylnitrosamine resulted in maximal inhibition of the initiation phase of hepatocarcinogenesis. This suggests but does not prove that the anti-carcinogenic activity of calcium glucarate was due to decreased liver proliferation. In the present study, the proliferation of ductular epithelial and oval cells appeared to be associated with the administration of diethylnitrosamine. Collectively, our data suggest that calcium glucarate inhibited the initiation phase of diethylnitrosamine-induced hepatocarcinogenesis.

Animals↗
PubMed1988

Preventive effect of 3-aminobenzamide on the reduction of NAD levels in rat liver following administration of diethylnitrosamine.

Nicotinamide adenine dinucleotide is utilized as the substrate of a chromatin-bound enzyme, poly(ADP-ribose) polymerase. The effects of diethylnitrosamine and/or 3-aminobenzamide, a potent inhibitor of poly(ADP-ribose) polymerase, on the cellular NAD levels in rat liver were investigated. 3-Aminobenzamide (600 mg/kg) administered intraperitoneally was not detectable in the liver within 12 hr after administration; the inhibitor had a calculated half life of 90 min. Diethylnitrosamine reduced the NAD levels in rat liver in a dose-dependent way. The NAD content reached a minimum level at 8 hr, returning to 78% of the control value after 48 hr. The reduction of the NAD levels caused by diethylnitrosamine was completely prevented when 3-aminobenzamide was administered either simultaneously with diethylnitrosamine or 4 hr after diethylnitrosamine treatment. Furthermore, an immunohistochemical study showed that nuclear poly(ADP-ribose) decreased 1 hr after the administration of 3-aminobenzamide. These results suggest that inhibition of poly(ADP-ribosyl)ation is involved in the initiation of liver carcinogenesis by diethylnitrosamine and 3-aminobenzamide.

Animals↗
PubMed1979

Prolonged induction of hepatic ornithine decarboxylase and its relation to cyclic adenosine 3':5'-monophosphate-dependent protein kinase activation after a single administration of diethylnitrosamine.

After a single injection of diethylnitrosamine (200 mg/kg), there was a rapid increase in the activity ratio of hepatic cyclic adenosine 3':5'-monophosphate (cyclic AMP)-dependent protein kinase (within 1 hr) followed by the induction of ornithine decarboxylase which was detectable by 3 hr. Both the cyclic AMP-dependent protein kinase activity ratio and the activity of ornithine decarboxylase were significantly elevated above controls for 7 days following the administration of diethylnitrosamine. A single noncarcinogenic dose of diethylnitrosamine (25 mg/kg) did not increase the cyclic AMP-dependent protein kinase activity ratio or induce ornithine decarboxylase activity at 24 hr postadministration. However, serial administration of diethylnitrosamine (25 mg/kg) for 4 or 7 days resulted in an increased activity ratio of cyclic AMP-dependent protein kinase and increased ornithine decarboxylase activity. This is the first report of a prolonged increase in both the activity ratio of hepatic cyclic AMP-dependent protein kinase and the activity of ornithine decarboxylase in response to a single carcinogenic dose of diethylnitrosamine.

Animals↗
PubMed1988

Action of phenobarbital given to rats together with diethylnitrosamine on the O6-ethylguanine content of liver DNA.

When rats are fed diethylnitrosamine (10 mg/kg/day), no O6-ethylguanine is found in liver DNA after 2 weeks, but a considerable amount accumulates after 4 weeks. On the other hand, a 2-week feeding of diethylnitrosamine is not sufficient to induce liver cancers, whereas a 4-week treatment leads to hepatocarcinomas in 50% of the animals. Administration of phenobarbital (75 mg/kg/day) together with diethylnitrosamine during 4 weeks prevents the formation of liver cancers. It also prevents accumulation of O6-ethylguanine in liver DNA. Phenobarbital does not change the amount of O6-ethylguanine repair activity present in liver chromatin after 2 or 4 weeks of treatment with diethylnitrosamine. It is thus concluded that, by inducing the development of the endoplasmic reticulum, phenobarbital decreases the equilibrium concentration of the ultimate carcinogen derived from this indirect alkylating agent.

Animals↗
PubMed1998

Time course of cell cycle-related protein expression in diethylnitrosamine-initiated rat liver.

BACKGROUND/AIMS: Cell cycle control and the relationship that exists between cellular proliferation, the expression of cell cycle control proteins and cancer have been reported. This study was designed to decipher the timing of cell cycle control protein expression during the initiation of diethylnitrosamine-induced rat hepatocarcinogenesis. METHODS: Three-week-old female Sprague-Dawley rats were intraperitoneally injected twice in 1 week with diethylnitrosamine; after the second injection, all animals were sacrificed at 1, 2 and 24 h, and 3 and 7 days. The expression of cell cycle-related proteins such as CDK2 and 4, cyclin proteins (D1, E and cdc2), proliferating cell nuclear antigen, tumor suppressor proteins (p53 and Rb), CDK inhibitory proteins (p21waf1 and p27Kip1), and apoptosis-inhibiting protein (bcl-2) following diethylnitrosamine treatment was examined. RESULTS: The peak induction time of each cell cycle-related protein during DEN-induced cellular proliferation was diverse, and expressions of CDK2, CDK4, cdc2, p53, bcl-2, p21Waf1 and p27Kip1 appear to be of the greatest interest. CONCLUSIONS: Data generated from this study may provide information about cell cycle-related protein expression in the initiation stage of hepatocarcinogenic signaling pathways stimulated by a genotoxic agent such as diethylnitrosamine.

Animals↗
PubMed1981

Lung endocrine-like cells in hamsters treated with diethylnitrosamine: alterations in vivo and in cell culture.

Diethylnitrosamine is known to cause squamous cell carcinoma and adenocarcinoma of the lung in Syrian golden hamsters. Sections of lungs obtained from hamsters treated with the systemic carcinogen diethylnitrosamine showed a significant increase in the number of argyrophilic cells of neuroepithelial bodies. The hyperplastic response was retained at least 4 weeks after cessation of treatment. To examine whether these affected cells exhibited enhanced survival in vitro, lung cells were dissociated with Pronase and grown in culture. After 7 days, argyrophilia, dense-cored vesicles, and corticotropin-like immunoreactivity were observed in many of the cells derived from hamsters treated for 5 or 8 weeks. These findings suggest that the endocrine-like cells of neuroepithelial bodies are affected by diethylnitrosamine as evidenced by a numerical increase in vivo and by the properties exhibited by cells in vitro. The relationship of this diethylnitrosamine-induced reaction to bronchial carcinoid tumors or small-cell carcinoma of the lung remains to be established.

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↗
PubMed1981

Role of acute hepatic necrosis in the induction of early steps in liver carcinogenesis by diethylnitrosamine.

Experiments were performed to assess the role of liver cell necrosis in the induction of early steps in liver carcinogenesis with diethylnitrosamine, as measured by the appearance of foci of resistant hepatocytes that stain for gamma-glutamyl transpeptidase and that are presumptive preneoplastic lesions in the rat. With the use of a necrogenic dose of diethylnitrosamine and an assay for the carcinogen-induced early stages or resistant hepatocytes, the number of enzyme-altered foci was decreased to a major extent (up to 62%) by posttreatment with diethyldithiocarbamate, a derivative of disulfiram. Such posttreatment decreased to a large degree (78%) the cumulative labeling index of hepatocytes following an initial exposure to diethylnitrosamine. The performance of partial hepatectomy up to 68 hr after such posttreatment restored the level of induction of the resistant hepatocytes. Nonnecrogenic doses of diethylnitrosamine or dimethylnitrosamine induced virtually no foci of resistant hepatocytes but did so when coupled with cell proliferation. These results establish clearly an important role for liver cell necrosis in the production of early steps in liver carcinogenesis in one model. The mechanism for this effect appears to be by the induction of compensatory liver cell proliferation.

Animals↗
PubMedDate not supplied

Chemoprevention of diethylnitrosamine-induced liver foci and hepatocellular adenomas in C3H mice.

The ability of six proposed chemopreventive agents to prevent diethylnitrosamine-induced liver foci and tumors in male C3H mice was investigated. The test agents were administered by intraperitoneal injection on days 13, 14 and 15 of age and starting at 21 days of age continuously in the diet until sacrifice at 161 days of age. The mice were administered 4.0 mg/kg diethylnitrosamine by intraperitoneal injection on day 15 of age and two hours after the test agent. Diethylnitrosamine-induced 62.4 +/- 4.2 foci of altered hepatocytes and 22.1 +/- 2.1 hepatocellular adenomas, which were reduced by diallyl sulfide to 21.6 +/- 2.4 and 6.73 +/- 1.13 and phenethyl isothiocyanate to 28.2 +/- 3.4 and 5.06 +/- 1.53 foci and adenomas, respectively. Difluoromethylornithine and ellagic acid only decreased the yield of adenomas without affecting the yield of foci of altered hepatocytes and of total lesions. N-Acetyl-l-cysteine and 1,2-oxothiazolidine-4-carboxylate did not affect the yield of either liver lesion. When administered starting prior to diethylnitrosamine-initiation and continuing until sacrifice, diallyl sulfide and phenethyl isothiocyanate demonstrated chemoprevention of tumorigenesis.

Adenoma↗
PubMed1973

The effects of diethylnitrosamine on ribonucleic acid and protein synthesis in the liver and lung of the Syrian golden hamster.

1. Syrian golden hamsters were treated with a single subcutaneous dose of 200mg of diethylnitrosamine/kg. In the liver the treatment produced a significant and early inhibition of the incorporation of orotic acid into RNA and of leucine into protein. Diethylnitrosamine also lowered basal and 20-methylcholanthrene-stimulated activities of hepatic aryl hydrocarbon hydroxylase. 2. RNA synthesis, protein synthesis and aryl hydrocarbon hydroxylase activity were also evaluated in the lungs of the same animals. In this organ only protein synthesis was affected by diethylnitrosamine, but not RNA synthesis or aryl hydrocarbon hydroxylase activity. 3. The incorporation of thymidine into DNA was inhibited in both organs early after diethylnitrosamine treatment and increased 2-3 days later. 4. Although diethylnitrosamine, injected subcutaneously, accumulates in liver and lung in toxicologically active amounts, the acute biochemical responses of the two organs are not identical.

Animals↗
PubMedDate not supplied

Chronic alcoholism enhances hepatocarcinogenicity of diethylnitrosamine in rats fed a marginally methyl-deficient diet.

To determine whether the chronic consumption of ethanol was capable of enhancing the hepatocarcinogenic activity of diethylnitrosamine per se, or through the accentuation of a methyl deficiency, two groups (A and B) of Sprague-Dawley female rats were fed for 10 months either a 20% casein basal diet marginally deficient in methyl, or the same diet supplemented with choline (1 gm per 100 gm) and folic acid (0.54 mg per 100 gm). Both groups were offered a drinking ethanol solution, while two other nonalcohol control groups (C and D) were isocalorically pair-fed to Groups A and B, and received diets in which the alcohol consumed by the corresponding groups was replaced by isocaloric amounts of sucrose. A baseline nonalcohol Group E, isocalorically pair-fed to Group A, received the intact basal diet of Group A and water. One day before the initiation of the experiment, and again 2 months later, all rats from the five groups were injected with a single i.p. dose of diethylnitrosamine (100 mg per kg). The growth attained by all groups was statistically similar. Hepatic triglycerides in Group A were significantly higher than in all the other groups. While in Group A primary hepatocellular carcinomas and renal tumors were encountered at the end of the experiment in 3 of 6 and in 2 of 6 rats, respectively, no malignancies were observed in any of the other groups. These results indicate that chronic ethanol consumption enhances the hepatocarcinogenic and renal tumorigenic activity of diethylnitrosamine, and strongly suggest that this action is mediated through the accentuation of methyl deficiency.

Alcoholism↗
PubMed1979

Sequential changes in DNA polymerases alpha and beta during diethylnitrosamine-induced carcinogenesis.

It has often been suggested that the high molecular weight DNA polymerase alpha of eukaryotes plays a role in de novo replication of DNA, while the low molecular weight polymerase beta is involved in repair replication. Previous studies have shown that when diethylnitrosamine is fed in the diet to rats it causes after a few weeks an increase in de novo replication of DNA, which then returns to normal values. In contrast, repair replication may be expected to continue throughout the feeding period. Study of DNA polymerase activity in livers of animals during carcinogenesis showed that an increase in polymerase alpha occurred at the time of increased de novo replication, while there was a gradual increase in polymerase beta during the time diethylnitrosamine was present in the diet. When diethylnitrosamine treatment was stopped, there was a rapid drop in polymerase beta activity. These results support the view that the polymerase alpha is involved in DNA replication, that the polymerase beta functions in repair replication, and that the beta enzyme can be induced by chronic damage to DNA.

Animals↗
PubMed1995

Low dose exposure of diethylnitrosamine affects mice liver thymidine kinase.

Swiss albino mice exposed to 5 and 10 mg diethylnitrosamine kg-1 body weight by intravenous route up to four weeks showed cyto- and genotoxic effects. Distortion of cell and nucleus shapes and extensive necrosis were observed. Thymidine kinase activity in the liver declined in diethylnitrosamine dose and duration dependent manners. The adult-form of thymidine kinase isozyme declined continuously during this period. Simultaneously, two isozymic forms of thymidine kinase, with small anodic migrations in an electrophoretic field, were gradually induced. Significance of theses changes in diethylnitrosamine induced precarcinogenic toxicity has been discussed.

Animals↗
PubMed1983

Formation of N-alkylated protoporphyrin IX in the livers of mice after diethylnitrosamine treatment.

The administration of di[1-14C]ethylnitrosamine to phenobarbital-pretreated mice resulted in the formation of a radiolabelled green pigment in their livers. Green-pigment concentrations were time- and dose-dependent, maximum levels being reached 1-2 h after dosing. There was only a slight decrease in cytochrome P-450 levels and accumulation of porphyrins in the liver at this time. Dimethyl- or dipropyl-nitrosamine also caused an accumulation of similar, though not identical, compounds in the liver. The formation of green pigment was induced by pretreatment of mice with phenobarbital or 3-methylcholanthrene and was inhibited by the acute administration of pyrazole or ethanol. From the absorption spectra, the green pigment methyl esters appeared to be N-alkylporphyrins. Analysis of the diethylnitrosamine-induced green pigment by high-pressure liquid chromatography showed it to be more polar than the expected N-ethylprotoporphyrin IX, having a retention time similar to that of N-hydroxyethylprotoporphyrin IX. Desorption chemical-ionization mass spectrometry gave a protonated molecular ion, m/z 635, compatible with N-hydroxyethylprotoporphyrin IX. The presence of a free hydroxy group was demonstrated by acetylation with [1-14C]acetic anhydride. No conversion of N-ethylprotoporphyrin IX into N-hydroxyethylprotoporphyrin IX could be demonstrated in vivo or in vitro. Little or no N-ethylprotoporphyrin IX accumulated in the livers of mice given diethylnitrosamine. It was concluded that N-hydroxyethylprotoporphyrin IX is the primary reaction product between an active metabolite of diethylnitrosamine and hepatic haem.

Animals↗