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PubMed2005

Effect of selenium-enriched malt on hepatocarcinogenesis, paraneoplastic syndrome and the hormones regulating blood glucose in rats treated by diethylnitrosamine.

233 SD rats weighing 100 approximately 120 g were divided randomly into 6 groups. The animals in group I and group II received 0.1 mg/kg selenium in the form of sodium selenite only and served as the negative control and positive control, respectively. Animals in groups III, IV and V were fed with selenium as Se-enriched malt supplemented diets (0.3, 1 and 3 mg/kg), and group VI with selenium by using sodium selenite supplemented diets (3 mg/kg). Animals of groups II approximately VI were induced hepatoma by diethylnitrosamine (100 mg/l) for 16 weeks, then drunk with sterilized water for 2 more weeks. Subsequently, the effects of Se-enriched malt and sodium selenite on hepatoma nodules, relative liver weight, the liver function indices including alanine aminotransferase (ALT), alkaline phosphatase (ALP), albumin (ALB), total bilirubin (TBIL), and the tumor markers, named as gamma-glutamyltranspeptidase (GGT), alpha-fetoprotein (AFP), insulin-like growth factor-II (IGF-II) were recorded. The calcium concentration, glucose content in plasma and values of the hormones regulating blood glucose, such as insulin, glucagons and thyroid hormones (3,5,3'-tetraiodothyronine, T(3); 3,5,3'5'-tetraiodothyronine, T(4)) were observed as well. At the same time, the correlations between the concentration of plasma glucose and related hormones were also analyzed. The results indicated that Se-enriched malt showed a better chemopreventive efficiency in decreasing the number of hepatoma nodules, relative liver weight and the contents of AFP, GGT, IGF-II, ALT, ALP and TBIL in the plasma, and delaying the descent of hormones in the serum, names as insulin, glucagons, T(3) and T(4) than those feeding with sodium selenite. Effect of Se-enriched malt excelled sodium selenite in the aspects of deadening the descent of glucose concentration in the plasma and the rise of calcium concentration in the serum of the rats with hepatoma induced by diethylnitrosamine. The values of glucose and calcium were significantly related to those items fore-named. In conclusion, the function of Se-enriched malt in deadening the lesion and delaying the development of hepatoma of rats induced by diethylnitrosamine was better than that of sodium selenite. Hypoglycemia and hypercalcemia were significantly correlated with the multifactors mentioned above.

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↗
PubMed1995

Dose dependence of diethylnitrosamine-induced nuclear enlargement in embryonal turkey liver.

Avian embryos (turkey) were exposed to diethylnitrosamine in ovo. On the first day of incubation doses of 0.5-5.0 mg/egg were injected into the white of the fertilized egg. The experiment was terminated 4 days before hatching. Livers were removed and prepared for subsequent histological examination. In haematoxylin and eosin stained sections the areas of hepatocyte nuclear profiles were measured by semi-automatic image analysis. In liver samples of diethylnitrosamine-exposed embryos hepatocyte nuclei of more than twice the size of normal hepatocyte nuclei were found. The incidence of the enlarged nuclei was clearly dose dependent. An increase in the size of hepatocyte nuclei was observed after low doses of diethylnitrosamine that did not induce common signs of non-specific toxic effects, e.g. cell death, fat vacuoles or loss of glycogen. The slope of the dose-response curve was rather steep. A 10-fold increase in the dose of the carcinogen resulted in a 100-fold increase in the incidence of enlarged hepatocyte nuclei. In combination with preneoplastic foci of altered hepatocytes, the quantification of nuclear enlargement can provide a valuable complementary parameter for the evaluation of carcinogen-induced effects in ovo.

Animals↗
PubMed1981

The induction of ornithine decarboxylase and DNA synthesis in rat hepatocytes after a single administration of diethylnitrosamine.

In primary monolayer culture of adult rat liver cells, the presence of a mixture of hormones stimulates DNA synthesis and proliferation. Under conditions of suboptimal hormone stimulation diethylnitrosamine was found to be effective in stimulation of DNA synthesis. Diethylnitrosamine also influences ornithine decarboxylase activity. The effect of some carcinogens and their structural related non-carcinogenic analogs on ornithine decarboxylase activity in primary cultured rat hepatocytes was studied. The addition of the carcinogens diethylnitrosamine, benzo[a]pyrene, methylmethanesulphonate and ethylmethanesulphonate caused significant increases in ornithine decarboxylase activity. Under the same conditions the non-carcinogenic analogs diethylformamide and pyrene did not show this change in enzyme activity.

Animals↗
PubMedDate not supplied

Diethylnitrosamine-induced hepatic tumors in wild vs. inbred strains of a viviparous fish.

A comparative study was made of the induction of hepatic tumors by diethylnitrosamine in 4 inbred strains, 3 hybrids from crosses between inbred strains, and 2 wild stocks of the viviparous fish Poeciliopsis lucida. Young fish, 1-36 days old, were administered diethylnitrosamine at concentrations of 25 ppm, 50 ppm, and 125 ppm for 3 to 5 successive 23-24-hour periods at one-week intervals. Primary neoplasms with histological characteristics of hepatocellular carcinomas were induced in fish exposed to 125 ppm of diethylnitrosamine for 3-5 successive periods at an incidence that increased from 58 percent to 93 percent directly with the number of exposures. They were not found in fish administered the lowest dose used (25 pm:3X) but a low incidence, 3-10 percent, occurred in fish receiving 3-5 exposures of the carcinogen at 50 ppm. No significant differences in tumor inducibility were found among the inbred strains, their hybrids, or the wild stocks.

Animals↗
PubMed1982

Effects of diethylnitrosamine on lung neuroendocrine cells.

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 revealed a significant increase in the number of argyrophilic cells of neuroepithelial bodies. These affected cells also exhibited enhanced survival in vitro. After 7 days in culture, argyrophilia, dense-core vesicles, and corticotropin-like immunoreactivity were observed in many of the cells derived from the lungs of carcinogen-exposed hamsters by dissociation with pronase. In addition, nuclei of argyrophilic cells in neuroepithelial bodies of the exposed hamsters were labeled at 60 min following administration of [3H]thymidine. This suggests that the carcinogen stimulates the pulmonary neuroendocrine-like cells to divide. Normally, the component cells of neuroepithelial bodies may originate from nonargyrophilic precursor cells in the surrounding epithelium, as in control hamsters the argyrophilic cells of neuroepithelial bodies appeared labeled only at 8 days after the administration of thymidine. The relationship of the diethylnitrosamine-induced reactions to bronchial carcinoid tumors or small-cell carcinomas of the lung remains to be established.

APUD Cells↗
PubMed1975

Factors affecting metabolism and mutagenicity of dimethylnitrosamine and diethylnitrosamine.

For exploration of the factors affecting dimethylnitrosamine (DMN) mutagenicity, for gathering of information on the metabolism of DMN, a frequently used and relatively well-understood carcinogen, and for explanation of metabolic variations in DMN carcinogenicity, parallel in vitro assays of the microsomal activation of DMN to a mutagen and of DMN demethylation were performed. Salmonella typhimurium G46 reversions to histidine independence increase linearly with time of incubation for 30 min. At low concentrations of microsomal protein, increases in protein yield a more than proportional increase in mutations. Increasing DMN concentration saturates the enzyme, yielding less demethylation and fewer mutations proportionately. Mutagenesis is completely inhibited by 1 mM 2-diethyl-aminoethyl-2,2-diphenylvalerate. When both DMN and microsomal protein are varied at high concentrations, there is a simple linear relationship between mutagenicity and DMN demethylase activity. Thus DMN demethylase activity may be the primary controlling factor in the metabolism of DMN to a mutagen, and probably to a carcinogen; other simultaneous pathways of DMN metabolism proportional to demethylation have not been ruled out. Induction with both phenobarbital and 3-methylcholanthrene (3-MC) increased rat and mouse liver DMN demethylase activity. Mouse liver microsomes from the C57BL/6 strain demethylate DMN at a markedly lower rate than do microsomes from the C3H strain, but after 3-MC induction the relationship is reversed. Strain differences in activation of DMN were not found in the activation of diethylnitrosamine to a mutagen. Hepatic dealkylation of DMN and diethylnitrosamine to active mutagenic metabolites is increased in both rats and mice by both 3-MC and phenobarbital induction, which is in contrast to the findings of others that 3-MC and phenobarbital induction, which is in contrast to the findings of others that 3-MC decreases the incidence of DMN-induced hepatic tumors in rats, and phenobarbital decreases the incidence of diethylnitrosamine-induced hepatic tumors in mice.

Animals↗
PubMed2005

[Effect of phenobarbital and thyroxine on hepatocarcinogenesis initiated in mice by nitrosoethylurea and diethylnitrosamine].

13-14-day old mice of ICR and CBA strains were given a single intraperitoneal injection of nitrosoethylurea (80 mg/kg) or diethylnitrosamine (50 mg/kg). 2 weeks later, they were given drinking water containing phenobarbital (1 g/L) or thyroxine (2 mg/L). The control mice were given only tap water. 29.4% of male and 42.1% of female ICR mice who had received nitrosoethylurea died of leukemia within 3-6 months after the carcinogen treatment. There was no case of leukemia in mice treated with diethylnitrosamine. Nitrosoethylurea induced 3-more often lung adenomas than diethylnitrosamine. Phenobarbital and thyroxine did not affect development of either leukemias or lung adenomas. By contrast, phenobarbital significantly elevated the number and size of hepatic lesions, whereas thyroxine markedly decreased them in all the experiments. The total and free thyroxine levels were significantly decreased in the blood of mice given phenobarbital and increased in mice given thyroxine. The data obtained indicate that thyroid hormones suppress tumor development in the mouse liver and that the promotion of hepatic tumoro-genesis by phenobarbital is presumably caused by the elimination of this suppressing effect of the thyroid hormones.

Alkylating Agents↗
PubMed1977

Altered cobalamin distribution in rat hepatomas and in the livers of rats treated with diethylnitrosamine.

The distribution of cobalamin cofactors was investigated in the livers and tumors of rats bearing transplanted Morris 7777 or 7800 hepatomas, in the livers of rats treated with the hepatocarcinogen diethylnitrosamine, and in normal rats. There was a significant increase in the proportion of methylcobalamin both in livers and tumors from rat bearing the hepatomas 7777 and 7800 compared to the proportion of methylcobalamin in the livers of normal rats. The total cobalamin content of the hepatomas was significantly lower than that of host or control livers. Similarly, the total cobalamin content of the livers from the tumor-bearing rats was less than that in control animals. The administration to rats of an acute dose of diethylnitrosamine led to an 84% increase in the hepatic concentration of methylcobalamin. Chronic administration of diethylnitrosamine slightly increased the hepatic methylcobalamin concentration, but this was not statistically significant. Liver weight was reduced, and the hepatic content of total cobalamin fell to 55% of that in control animals.

Animals↗
PubMed1983

Presence of alpha-fetoprotein-positive cells in hepatocellular foci and microcarcinomas induced by single injections of diethylnitrosamine in infant mice.

Single injections of diethylnitrosamine (5 and 50 micrograms/g body weight) in male C57BL/6J X C3HeB/FeJ F1 mice when they were 15 days old resulted in the induction of RNA-rich hepatocellular foci and nodules that contained alpha-fetoprotein (AFP)-positive hepatocytes after 20 and 28 weeks. The focal lesions were composed of 1- to 2-cell-thick plates of hepatocytes or closely packed clusters of cells, but they did not show the histological patterns that are diagnostic of trabecular hepatocellular carcinoma. AFP-positive hepatocytes were found in almost one-fourth (14 of 60) of the foci and nodules in a serially sectioned block of liver from a mouse given one injection of 50 micrograms/g body weight diethylnitrosamine and killed at 28 weeks. In general, the presence or absence of AFP-positive cells correlated with the size of the foci and nodules. All six nodules with diameters greater than 1.5 mm contained AFP-positive cells, while all 12 foci smaller than 0.24 mm in diameter were negative for AFP. However, among the 42 foci that were intermediate in size, there were 8 AFP-positive foci, the sizes of which appeared rather randomly distributed among the negative foci. Reactive changes in hepatocytes could be ruled out as a cause of the induction of AFP because the foci first appeared many weeks after the administration of diethylnitrosamine in these mice. Since bile ductules or oval cells, which occasionally appeared in these foci, were lacking entirely in AFP and since ductules are absent from the early-appearing and smallest foci, we believe that in this model the AFP-positive foci arise only from hepatocytes. The presence of AFP in the focal lesions and in tumor thrombi that extended from them into hepatic vein branches supports the hypothesis that some foci undergo progression to invasive microcarcinomas and that these in turn are precursors of late-appearing (after 1 year) metastasizing trabecular hepatocellular carcinomas.

Animals↗
PubMed1994

Enhancement by organosulfur compounds from garlic and onions of diethylnitrosamine-induced glutathione S-transferase positive foci in the rat liver.

Ten organosulfur compounds from garlic and onions were studied for their modifying effects on diethylnitrosamine-induced neoplasia of liver in male F344 rats using the medium-term bioassay system of Ito based on the two-step model of hepatocarcinogenesis. Carcinogenic potential was scored by comparing the number and area per cm2 of induced glutathione S-transferase placental form-positive foci in the liver with those of the corresponding control group given diethylnitrosamine alone. In experiments 1 and 2, high doses of diallyl sulfide, diallyl trisulfide, allyl methyl sulfide, allyl methyl trisulfide, and dipropyl sulfide had enhancing effects on focus formation. In contrast, high doses of methyl propyl disulfide and propylene sulfide significantly decreased the number of glutathione S-transferase placental form-positive foci. In the third experiment, combined treatment with the five chemicals that had enhancing activity were fed at low doses and increased the induction of glutathione S-transferase placental form-positive foci. To investigate the mechanism of the modifying effect on hepatocarcinogenesis, ornithine decarboxylase activity was measured in diallyl sulfide-, allyl methyl sulfide-, and dipropyl sulfide-treated liver tissue without prior initiation with diethylnitrosamine, and its activity was increased compared to controls. Spermidine/spermine N1-acetyltransferase activity was not significantly changed. Formation of 8-hydroxydeoxyguanosine, a DNA adduct generated by activated oxygen species, and lipid peroxidation (2-thiobarbituric acid-reacting substance production) were also not changed. These results suggest that the promoting effect could be caused by increased cell proliferation with increased polyamine biosynthesis. In evaluating relationships between diet and cancer, it is appropriate to consider not only the possible protective role of garlic and onions but also their enhancing effects.

Allium↗
PubMed1971

Nitrosamine-induced carcinogenesis. The alkylation of N-7 of guanine of nucleic acids of the rat by diethylnitrosamine, N-ethyl-N-nitrosourea and ethyl methanesulphonate.

1. The extent of ethylation of N-7 of guanine in the nucleic acids of rat tissue in vivo by diethylnitrosamine, N-ethyl-N-nitrosourea and ethyl methanesulphonate was measured. 2. All compounds produced measurable amounts of 7-ethyl-guanine. 3. A single dose of diethylnitrosamine or N-ethyl-N-nitrosourea produced tumours of the kidney in the rat. Three doses of ethyl methanesulphonate produced kidney tumours, but a single dose did not. 4. A single dose of diethylnitrosamine produced twice as much ethylation of N-7 of guanine in DNA of kidney as did N-ethyl-N-nitrosourea. A single dose of both compounds induced kidney tumours, although of a different histological type. 5. A single dose of ethyl methanesulphonate produced ten times as much ethylation of N-7 of guanine in kidney DNA as did N-ethyl-N-nitrosourea without producing tumours. 6. The relevance of these findings to the hypothesis that alkylation of a cellular component is the mechanism of induction of tumours by nitroso compounds is discussed.

Alkanes↗
PubMed1975

Effect of diethylnitrosamine on the livers of rats after high oral doses administered at intervals varying between three and twenty-four days.

When 200 mg of diethylnitrosamine per kg of body weight was administered with a stomach tube once a week to female Wistar W.64 rats, all of them died within three weeks from severe hepatocellular injuries and haemorrhages of the liver, lungs and small intestine. Weekly administrations of 100 mg per kg of body weight consistently caused the rats to die after seven to fifteen weeks from severe hepatic cirrhoses characterized by large tubercles. Weekly doses of 50 mg per kg of body weight caused much less severe hepatic cirrhosis. Under these conditions death occurred after 17 to 23 weeks, all the rats having contracted multiple hepatocellular carcinomas and in most cases pronounced hepatic cirrhosis. When this amount of diethylnitrosamine was administered for twelve weeks only the hepatic cirrhosis was less apparent, but a substantial influence on the tumor development was not observed. After a reduction of the dose to 25 mg per kg of body weight once a week all the rats in the relevant group died after 26 to 35 weeks, likewise from multiple hepatocellular carcinomas. Hepatic cirrhosis were then relatively inconspicuous. Similar results were obtained when, not the dose, but the interval between doses (100 mg/kg each) was varied. This clearly differential effect of diethylnitrosamine in the rat thus makes it a simple matter to induce hepatic cirrhosis or cancers that are suitable for a variety of tests and also, for example, as models for therapy trials.

Animals↗
PubMed2005

Effect of neonatal injection of sodium glutamate and diethylnitrosamine on hepatocarcinogenesis, reproductive and adrenocortical systems of male mice.

Neonatal injection of sodium glutamate before injection of diethylnitrosamine decreased the number of tumor nodes in the liver of male mice, decreased the weight of the testes and adrenals and blood level of testosterone (but increased blood level of corticosterone), impaired recovery of diethylnitrosamine-disturbed sexual motivation in half of males. Anticarcinogenic effect of sodium glutamate is explained by feminization of males under its effect.

Adrenal Glands↗
PubMed1975

Acute biochemical and morphological effects of N-nitrosomorpholine in comparison to dimethyl- and diethylnitrosamine.

Some biochemical and ultrastructural changes induced in the livers of rats treated with N-nitrosomorpholine are described and compared with parallel observations in rats given dimethyl- or diethylnitrosamine. Hepatotoxic doses of the nitrosamines caused inhibition of incorporation of [14C]leucine into hepatic proteins, accompanied by progressive disaggregation of polysomes which paralleled the known time course of metabolism of each compound. Dimethylnitrosamine (DMN) and N-nitrosomorpholine (NM) inhibited incorporation of [14C]orotate into liver RNA but diethylnitrosamine (DEN) caused a slight stimulation of orotate incorporation. Electron microscopy revealed similar hepatic cytoplasmic changed induced by each nitrosamine, including dilation and degranulation of the rough surfaced endoplasmic reticulum and subsequent increase of the smooth endoplasmic reticulum. Nuclear changes differed with each compound, N-nitrosomorpholine having more marked effects than either dialkyl compound. The results are discussed with particular reference to the metabolism of N-nitrosomorpholine in the liver.

Animals↗
PubMed1988

Increased hepatic androgen receptor expression in female rats during diethylnitrosamine liver carcinogenesis. A possible correlation with liver tumor development.

This study investigated the relationship between liver tumor development and androgen-receptor expression in diethylnitrosamine hepatocarcinogenesis in Wistar rats (SUAH substrain). Random liver samples were assayed by an isoelectric focusing method, with [3H]mibolerone as androgenic radioligand. After 16 wk of oral diethylnitrosamine treatment there was a greater than 20-fold increase in hepatic androgen receptor concentration in female rats (control group 0.3 +/- 0.07 fmol/mg cytosol protein; test group 8.36 +/- 0.96 fmol/mg cytosol protein; p less than 0.001, unpaired Student's t-test). This coincided with, and may be related to, an accelerated development of neoplastic nodules or hepatocellular carcinoma, or both. Male rats showed slower tumor development and no change in androgen receptor concentrations. This model is the first to demonstrate significantly increased androgen sensitivity in experimental hepatic carcinogenesis analogous to increased androgen receptor expression in human hepatocellular carcinoma. It may provide insight into steroid hormone sensitivity in developing tumors, and a means of testing potential therapeutic use of hormonal manipulation in human liver cancer.

Animals↗
PubMed1995

Damage to mitochondrial DNA induced by the hepatocarcinogen diethylnitrosamine in ovo.

Different doses of the hepatocarcinogen diethylnitrosamine (DEN) were injected into fertilized turkey eggs 8 days before hatching. The embryos were removed from the eggs after 4 days and liver samples were shock frozen. Mitochondrial DNA (mtDNA) was purified from the samples. Electrophoresis on agarose gels with native mitochondrial DNA and with ribonuclease-treated mitochondrial DNA revealed a DEN-induced effect on the molecular size of the mtDNA. The content of mtDNA of the regular size of 16 kb dose-dependently decreased, whereas the amount of mtDNA fragments of various size increased. Fluorescent staining of the electrophoresis gels allowed the densitometric quantification of the mitochondrial DNA of the regular band at 16 kb and the amount of fragments of irregular size (smear). The diethylnitrosamine-induced effect was dose-dependent over the whole dose range from 1.24 to 6.2 mmol/kg. Even the lowest dose (10 mg DEN per egg) showed clear-cut effects. Mitochondrial damage and malfunction may be mechanistically involved in the neoplastic transformation and in aging phenomena. The in ovo model is a simple and rapid approach for investigations on chemically induced alterations of mtDNA.

Animals↗
PubMedDate not supplied

Effect of phenobarbital on diethylnitrosamine and dimethylnitrosamine induced hepatocellular tumors in male B6C3F1 mice.

The effect of the type of carcinogen initiator on the ability of phenobarbital (PB) to promote hepatic tumor formation in 15-day-old initiated male B6C3F1 mice was evaluated. Fifteen-day-old male B6C3F1 mice were divided into 6 groups of 10 mice each. Groups 1 and 2 received a single intraperitoneal (i.p.) injection of diethylnitrosamine (DENA) (5 micrograms/body wt). Groups 3 and 4 received a single i.p. injection of diethylnitrosamine (DENA) (5 micrograms/g body wt). Groups 3 and 4 received a single i.p. injection of dimethylnitrosamine (DMNA) (5 micrograms/g body wt). Groups 5 and 6 received a single i.p. injection of saline. At weaning (28 days of age), mice in groups 2, 4 and 6 received PB (500 mg/ml) in their drinking water. Mice in groups 1, 3 and 5 received deionized drinking water. Drinking water treatment continued for 24 weeks at which time mice were sampled. At sampling, mice were examined for hepatic tumors by histology. Mice in groups 5 (no treatment) and 6 (PB only) did not exhibit hepatic tumors. Groups 2 (DENA + PB) displayed a decrease in hepatic adenomas from that of group 1 (DENA only), confirming previous observations. Treatment with DMNA and PB (group 4), however, resulted in a significant increase in both hepatic adenoma incidence and number over that of DMNA only (group 3) treated mice. The promoted adenomas appeared to be predominantly eosinophilic in appearance. The type of initiator therefore appears important in determining if 15-day-old initiated male B6C3F1 mice respond to the promotion effects of PB.

Adenoma↗