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PubMed1985

Methylated purines formed in DNA by dimethylnitrosamine in rats previously exposed to hepatotoxic and hepatocarcinogenic regimes: effects on the repair of O6-methylguanine.

Studies of mammalian systems for the repair of O6-methylguanine in DNA have revealed large differences in the capacities of tissues and cells to perform this function and in the case of rat liver it has been shown that the O6-methylguanine repair system can be stimulated by exposure to hepatotoxic and hepatocarcinogenic regimes. In this report an assessment is made of possible relationships between toxic liver injury, DNA synthesis, cell proliferation and DNA repair by treating Wistar rats with agents selected to provide differing degrees of liver involvement. The effects of long-term (20 week) treatments with acetylaminofluorene (15 mg/kg/day), quinoxaline 1,4-dioxide (10 mg/kg/day), 4-aminobiphenyl-HCl (15 mg/kg/day) and pronethalol (20 mg/kg/day) were assessed, using the same strain of animals in which the original toxicity and carcinogenicity data were obtained. Repair of O6-methylguanine produced in liver DNA by a low, non-toxic dose (2 mg/kg) of [14C]dimethylnitrosamine was increased 3-4-fold throughout the period of treatment with acetylaminofluorene, to a lesser extent by quinoxaline 1,4-dioxide and 4-aminophenyl-HCl and not at all in the case of pronethalol. No evidence was obtained to indicate a direct relationship between O6-methylguanine repair and either the induced hepatotoxicity or the ensuing increased rates of DNA synthesis which occur following exposure to these agents.

2-Acetylaminofluorene↗
PubMed2003

Ascorbic acid concentrations in dimethylnitrosamine-induced hepatic fibrosis in rats.

BACKGROUND: Ascorbic acid is a potent antioxidant and is involved in many metabolic activities including collagen biosynthesis. In the present investigation, ascorbic acid and lipid peroxides were monitored in the blood and liver samples during the progression of experimentally induced hepatic fibrosis. METHODS: Liver injury was induced by intraperitoneal injections of dimethylnitrosamine (DMN) on three consecutive days of every week over a period of 21 days. The progression of fibrosis was assessed by histopathological examination and by monitoring of the collagen content of the liver tissue. Ascorbic acid and lipid peroxides were monitored in both blood and liver samples on days 0, 7, 14, and 21 after the start of DMN administration. The liver total protein was also measured during the investigation. RESULTS: Histopathological examination demonstrated centrilobular necrosis, fibrosis, and early cirrhosis during DMN treatment. The collagen content increased four-fold on the 21st day of investigation. Lipid peroxides were elevated significantly in both blood and liver specimens on days 7, 14, and 21. A drastic decrease was observed in the ascorbic acid concentrations in both liver and blood samples on all days after the start of DMN administration. Liver total protein concentrations were significantly reduced during DMN administration. CONCLUSIONS: The exact mechanism of the decrease of ascorbic acid during DMN-induced hepatic fibrosis is not clear. The most probable reason for the decreased blood and liver ascorbic acid during DMN-induced hepatic fibrosis is the increased utilization of ascorbic acid for free radical scavenging in order to reduce the highly elevated oxidative stress.

Animals↗
PubMed2000

Biochemical abnormalities during the progression of hepatic fibrosis induced by dimethylnitrosamine.

OBJECTIVES: The pathogenesis of hepatic fibrosis is accompanied with several biochemical and metabolic abnormalities. To obtain more information about the alteration of biochemical and metabolic parameters during alcoholic liver fibrosis, we have monitored the changes of certain important biochemical compounds in experimentally induced hepatic fibrosis. DESIGN AND METHODS: The liver injury was induced in adult male albino rats by using dimethylnitrosamine (DMN) in doses of 1 mg/100 g body weight. Total collagen, total protein, cholesterol, lipid peroxides, glucose, urea, and inorganic phosphorus were monitored in liver and blood/serum samples on Days 0, 7, 14, and 21 after the start of DMN administration. Serum insulin levels were assayed by radioimmunoassay. The serum and urinary levels of hydroxyproline, uric acid, and creatinine were also monitored. RESULTS: The total collagen content in the liver was increased about 4-fold by Day 21 after the start of DMN administration. A significant increase was observed in lipid peroxide levels in both liver and blood samples. Although inorganic phosphorus level decreased in both serum and liver tissue, cholesterol was lowered only in the serum. Increased serum insulin level with impaired glucose tolerance was observed after 21 days. Serum hydroxyproline level increased throughout after the start of DMN administration. The urinary excretion of hydroxyproline was also significantly increased with a striking elevation on Day 7. Elevated uric acid levels were recorded in serum and urine samples during the latter periods of DMN treatment. No alteration was observed in blood urea and creatinine levels. CONCLUSIONS: The results of the present investigation demonstrated important alterations in metabolic parameters and biochemical abnormalities during experimentally induced liver damage. All alterations are compatible with the deterioration of liver functions during the pathogenesis of hepatic fibrosis.

Animals↗
PubMed2000

Mutant frequencies and mutation spectra of dimethylnitrosamine (DMN) at the lacI and cII loci in the livers of Big Blue transgenic mice.

The lacI gene in Big Blue transgenic rodents has traditionally been used as a surrogate gene for in vivo mutations. Recently, a more efficient and less expensive assay involving direct selection in the smaller lambda cII gene has been developed. Little is known, however, about the comparative sensitivity of the two loci or their influence on the recovered mutation spectrum following mutagen treatment. We have compared the mutation frequency (MF) and mutational spectrum (MS) of lacI and cII from the same DNA samples isolated from the liver of control and dimethylnitrosamine (DMN)-treated mice. A three-fold (p<0.01) increase in the MF was observed at both loci in the DMN-treated group compared to the corresponding control groups. While the DMN-induced mutation spectrum at lacI was significantly different from its corresponding spontaneous mutation spectrum (p<0.001), the mutation spectrum at cII (p>0.28) was not. The mutation spectra at the two loci from the DMN-treated mice resembled each other but the 4, 2.5 and 12-fold increase in the mutation frequency of A:T>T:A transversions, single base deletions and deletions of more than four base pairs, respectively, at lacI, altered the spectra significantly (p<0.007). The number of mutations of these classes at cII was also increased, but the fractions were lower than at lacI. The spontaneous mutation spectra at the cII and lacI loci resembled each other except for the seven-fold increase in G:C<C:G transversions in the cII spectrum resulting in a significant difference (p<0.0001) between the spectra. Our initial data indicates that although cII is as sensitive to mutation induction as lacI, fewer sites are available for certain classes of mutations to be manifest resulting in an apparent lack in change in the mutation spectrum.

Animals↗
PubMed2001

A selective ROCK inhibitor, Y27632, prevents dimethylnitrosamine-induced hepatic fibrosis in rats.

BACKGROUND: p160ROCK is a direct Rho target which mediates Rho-induced assembly of focal adhesions and stress fibers. We previously reported that Rho signaling pathways are involved in the activation of hepatic stellate cells (HSC) in vitro. The aim of the present study was to test the hypothesis that an inhibitor specific for p160ROCK (Y27632) could prevent experimental hepatic fibrosis induced by dimethylnitrosamine (DMN) in rats. METHODS: Y27632 was given orally at 30 mg/kg daily for 4 weeks after the first injection of DMN. The degree of fibrosis was evaluated by image analysis and also by measurements of collagen and hydroxyproline content in the liver. The expression of alpha-smooth muscle actin (alpha-SMA) in the liver and in the primary cultured HSC was also evaluated. Semi-quantitative RT-PCR was performed to evaluate the expression of type I collagen mRNA in the liver. RESULTS: Y27632 treatment significantly decreased the occurrence of DMN-induced hepatic fibrosis and reduced the collagen and hydroxyproline content and alpha-SMA expression in the liver. The expression of alpha-SMA in HSC was also suppressed in vitro. CONCLUSIONS: These findings indicate that inhibitors of the Rho-ROCK pathway might be useful therapeutically in hepatic fibrosis.

Actins↗
PubMed1985

A dimethylnitrosamine-induced model of cirrhosis and portal hypertension in the rat.

A method of producing cirrhosis consistently in rats by the administration of dimethylnitrosamine (DMNA) is described. Two weeks following the cessation of DMNA treatment there was distortion of the lobular architecture of the liver and some focal nodule formation. This 'pre-cirrhotic' state was accompanied by portal hypertension, biochemical abnormalities and the development of ascites. The mortality 2 weeks after cessation of DMNA was 42%. Twenty-four weeks after DMNA treatment cirrhosis had developed with diffuse nodularity and fibrosis, marked portal hypertension, and accumulation of ascites. There was also a deterioration in liver function, with hypoproteinaemia and jaundice. The overall mortality 24 weeks after the cessation of DMNA treatment had risen to 52%. This model of cirrhosis in the rat may be useful in evaluating the efficacy of drugs in the long-term management of portal hypertension in man.

Animals↗
PubMed1987

A morphological study of the early stages of hepatic fibrosis induced by low doses of dimethylnitrosamine in the rat.

Hepatic fibrosis has been induced in rats by low doses of dimethylnitrosamine (DMN) and special attention has been paid to early morphological events. DMN (10 microliter/kg body wt., i.p.) was given 3 days a week for 3 weeks to Sprague-Dawley rats. Liver samples were taken on days 7, 14, 21, 28 and 35 and examined by light and electron microscopy. Hemorrhagic necrosis, mainly centrolobular, was evident on day 7, with disruption of the sinusoidal lining, and widening or disappearance of the spaces of Disse invaded by erythrocytes and lymphocytes. Large granular lymphocytes similar to pit cells were also present in close contact with hepatocytes. At day 14, fibrotic septa were associated with cells bearing 'transitional' features between those of lipocytes, myofibroblasts and fibroblasts. Hepatocytes showed foci of increased smooth endoplasmic reticulum, and altered sinusoidal and canalicular membranes. At day 21, all animals showed nodularity of the parenchyma, with evidence of micronodular cirrhosis associated with ascites in two animals. At day 35 (19 days after cessation of treatment) there was little residual inflammation, but well-defined micronodules were still present in all animals. This shows that, in the rat, 3-week treatment with a low dose of DMN produces micronodular cirrhosis following diffuse hemorrhagic necrosis without steatosis. The response of the animals was uniform and reproducible. Lesions of the sinusoidal wall and of membranes of liver cells associated with the inflammatory reaction appeared prominent.

Animals↗
PubMed1997

Halofuginone, a specific inhibitor of collagen type I synthesis, prevents dimethylnitrosamine-induced liver cirrhosis.

BACKGROUND/AIMS: Hepatic cirrhosis is characterized by excessive deposition of collagen, resulting from an increase in type I collagen gene transcription. We evaluated the effect of halofuginone-a specific inhibitor of collagen type alpha 1(I) gene expression-on dimethylnitrosamine (DMN)-induced liver fibrosis/cirrhosis in rats. METHODS: Fibrosis was induced by intraperitoneal injection of DMN. Halofuginone (5 mg/kg) was added to the diet. Collagen was stained with Sirius red and collagen alpha 1(I) gene expression was evaluated by in situ hybridization. RESULTS: In control rats, a low level of collagen alpha 1(I) gene expression was observed. A high dose of DMN (1%) caused severe fibrosis, as indicated by induction of collagen alpha 1(I) gene expression and increased liver collagen content. Addition of halofuginone before the onset of fibrosis, almost completely prevented the increase in collagen type I gene expression and resulted in lower liver collagen content. Moreover, halofuginone partially prevented the marked decrease in liver weight and reduced the mortality rate. At a lower dose of DMN (0.25%), which causes mild fibrosis, halofuginone prevented the increase in collagen alpha 1(I) gene expression, prevented the increase in liver collagen deposition and reduced plasma alkaline phosphatase activity, all of which are characteristic of liver fibrosis/ cirrhosis. CONCLUSIONS: These results suggest that halofuginone can be used as an important tool to understand the regulation of the collagen alpha 1(I) gene and may become a novel and promising antifibrotic agent for liver fibrosis/ cirrhosis.

Alkaline Phosphatase↗
PubMed1991

Immunohistochemical detection of DNA alkylation adducts in rat and hamster liver after treatment with dimethylnitrosamine.

Monoclonal and polyclonal antibodies specific for methylation adducts have been applied in an immunohistochemical study of DNA damage in rat and hamster liver following exposure to dimethylnitrosamine. The approach was validated, for frozen and paraffin-embedded sections, by comparison with biochemical data on adduct levels in whole tissues or specific cell populations in the same experimental systems. The potential application of this method to human exposure assessment is discussed.

Alkylation↗
PubMed2001

Dimethylnitrosamine-induced liver injury in rats: the early deposition of collagen.

Dimethylnitrosamine (DMN) is a potent hepatotoxin that can cause fibrosis of the liver. It's ability to provide a suitable rapid experimental murine model for early human cirrhosis was examined. The drug was administered to adult male albino rats in order to document sequential pathological and biochemical alterations. Injury was produced by intraperitoneal injections of DMN on three consecutive days of each week over a 3-week period. A rapid increase in collagen content was documented, with linear increases occurring from days 7 to 21. Livers were examined for histopathological changes on days 7, 14 and 21 following the beginning of exposure. Severe centrilobular congestion and haemorrhagic necrosis could be observed on day 7. Centrilobular necrosis and intense neutrophilic infiltration were observed on day 14. By day 21, collagen fiber deposition could be observed, together with severe centrilobular necrosis, with focal fatty changes, bile duct proliferation, bridging necrosis and fibrosis surrounding the central veins. A decrease in total protein and increase in DNA were also documented. DMN-induced liver injury in rats appears to be a potential animal model for early human cirrhosis and the rapid deposition of collagen, and may serve as a convenient procedure for screening antifibrotic agents.

Animals↗
PubMed1975

The carcinogenic effect of dimethylnitrosamine on the Chinese hamster (Cricetulus griseus).

Three groups of Chinese hamsters (20 males, 20 females/group) received weekly subcutaneous injections for life of dimethylnitrosamine (DMN) at dose levels 0.20, 0.10 and 0.05 of the LD50. Eighty-two to 100% of the animals developed tumors of vascular origin. The neoplasms were primarily hepatic hemangioendotheliomas and their incidence was unrelated to dose or sex. Although animals in the low dose group received a total dose which was one-third that of the highest dose group, their survival times were only slightly longer.

Animals↗
PubMed1975

The binding of dimethylnitrosamine to nucleic acids catalyzed by liver enzymic fractions.

The in vitro binding of a metabolite of dimethylnitrosamine (DMNA) to calf thymus DNA catalyzed by a microsomal system from rat liver is reported. The amount ob binding is unaffected by using microsomes induced by 3-methylcholanthrene and/or normal or induced pH 5 enzymes. The microsomal system is also effective in catalyzing covalent binding of the nitroso compound with synthetic polyribonucleotides.

Animals↗
PubMed1978

DNA repair synthesis in primary cultures of kidneys from BALB/c and C3H mice treated with dimethylnitrosamine.

A combined 'in vivo--in vitro' autoradiographic method was employed to examine the DNA repair induced in the kidney by a single dose of dimethylnitrosamine (DMNA). Unscheduled DNA synthesis was found to be dose-dependent in primary kidney cultures of DMNA-treated mice, and practically not detectable in controls. Its amount was positively correlated with the different susceptibility of C3H and BALB/c mice to kidney tumor induction by DMNA. This experimental model appears sensitive and able to provide repeatable results. It may be useful to detect the organotropic activity of a carcinogen toward the kidney.

Animals↗
PubMed1978

The carcinogenic effect of dimethylnitrosamine in laboratory bred European hamsters (Cricetus cricetus).

The carcinogenic effect of dimethylnitrosamine (DMN) s.c. injected at two different dose levels was studied in laboratory bred European hamsters (EH) and data compared to findings for captured EH. Malignant haemangioendotheliomas of the liver and kidney, hepatocellular carcinomas and cholangiocarcinomas were induced. In contrast to the results obtained with wild EH, a large number of the laboratory bred females additionally developed ovarian granulosa cell tumors.

Animals↗
PubMed1978

Hydroxyurea-sensitive thymidine incorporation in rat liver and kidney following administration of dimethylnitrosamine.

In rats treated with dimethylnitrosamine (DMN), the sensitivity of [3H] thymidine incorporation to inhibition by hydroxyurea was determined in the liver and kidney. A 70% inhibition was produced in control animals with doses of hydroxyurea from 50 to 250 mg/kg body wt. Twelve hours after administration of DMN, hepatic thymidine incorporation was unaffected by 50 mg/kg hydroxyurea, progressive reduction in incorporation occurred as the dose of inhibitor was increased. A similar result was obtained in kidney only by dietary conditioning of rats to ensure a high renal metabolism of the DMN. In contrast, at 72 h after DMN treatment thymidine incorporation in both liver and kidney was rapidly inhibited by administration of 50 mg/kg hydroxyurea. The data, assessed together with various parameters of DMN-induced repair and replicative DNA synthesis, suggest the use of hydroxyurea as a means to study DNA repair in intact animals.

Animals↗
PubMed1978

Effect of dimethylnitrosamine concentration on its demethylation by liver microsomes from control and 3-methylcholanthrene pretreated rats, hamsters and guinea pigs.

The effect of dimethylnitrosamine concentration on its demethylation by liver microsomes from control and 3-methylcholanthrene pretreated (100 mg/kg body wt. 24 h before sacrifice) rats, hamsters and guinea pigs was investigated. At low substrate concentration (2 mM), liver microsomes from pretreated rats and hamsters showed 30-50% lower demethylation activity than their respective controls. No such difference was found in the guinea pig. At high substrate concentration (100 mM), all 3 pretreated species showed 50-100% higher enzyme activity than their respective controls. Enzyme activities among the 3 species showed the following order of activity: hamster greater than guinea pig greater than rat.

Animals↗
PubMed1997

Comparative study on organ-specificity of tumorigenicity, mutagenicity and cell proliferative activity induced by dimethylnitrosamine in Big Blue mice.

Recently, we have shown that dimethylnitrosamine (DMN) treatments increase lacI mutant frequency in the liver, kidney and lung but not in other organs, and also enhance cell proliferation only in the bronchial epithelia. In the present study, organ specificity of tumorigenicity induced by DMN was compared to those of lacI mutation and cell proliferation in Big Blue mice. Male 8-week-old Big Blue mice were treated with daily i.p. injections of 1 or 10 mg/kg DMN for 5 days, or a single i.p. injection of 5 or 10 mg/kg DMN. Except for the 10 mg/kg x 5 DMN group, all animals survived until 78 weeks after the first treatment of DMN. In the present study, the induction of cell proliferation in the bronchial epithelia was confirmed in a dose-dependent manner. At the termination of 78 weeks, it was histopathologically shown that the DMN-treated mice developed liver cell tumor in three out of seven (43%) of the 5 mg/kg group, renal tubule dysplasia in three out of seven (43%) of the 1 mg/kg x 5 group, and duodenal adenocarcinoma in one of seven (14%) of the 1 mg/kg x 5 group, although no neoplastic or preneoplastic lesions were found in the control mice. Because non-transgenic C57BL/6 mice are resistant to developing spontaneous liver cell and duodenal tumors, it was speculated that even these low doses of DMN could be sufficient to initiate target cells. Our results thus suggest that organ specificity of tumorigenicity by DMN is in favorable agreement with that of lacI mutation but not with possibly temporal cell proliferation induced by DMN.

Animals↗
PubMed1998

Susceptibility of C57BL/6 mice to tumorigenicity induced by dimethylnitrosamine and 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine in the neonatal bioassay.

Male C57BL/6 neonates were treated on days 8 and 15 with 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP, 6.5 or 26.2 mg/kg) or dimethylnitrosamine (DMN, 2.6 or 10.5 mg/kg). No tumors were seen in PhIP-treated animals at 15 months of age. Liver and lung tumor incidences in DMN-treated animals were 67-79 and 0-7%, respectively. In comparison with data from other strains, our results indicate that (1) neonatally-treated C57BL/6 mice are resistant to the induction of liver and lung tumors by PhIP and lung tumors by DMN and (2) the susceptibility of this strain to induced liver tumors correlates with the activity of hepatic DMN N-demethylase and PhIP N-hydroxylase in the (untreated) neonates.

Animals↗