No abstract available.
Animals ; Carcinogenesis* ; Dimethylnitrosamine* ; Female* ; Humans ; Mice*

Carbon tetrachloride and dimethylnitrosamine, both potent hepatotoxic agents, affect the hepatic lobules with fatty changes and central necrosis, and hemorrhagic necrosis. To study the effects on morphologic changes of the hepatic lobules in cases of single and repeated treatment of both hepatotoxins, sublethal doses of carbon tetrachloride, 0.4ml/kg, and dimethyl nitrosamine, 40 mg/kg of rats were given introperitoneally single, twice and triple. With interval of 3 days, and the results were as follows: 1. The fatty changes and central necrosis of the hepatic lobules were milder and more quickly disappeared in the rats with twice or triple treatment than single administration of carbon tetrachloride, and regenerative changes of hepatic and sinusoidal cells achieved fater in the rats with repeated administration of carbon tetrachloride than those with single treatment. 2. The hemorrhagic necrosis of the hepatic lobules was not significantly influenced by the times of DMN treatment, but the hyperplastic changes showed more active to animals, with multiple administration of DMN.
Animals ; Carbon Tetrachloride* ; Carbon* ; Dimethylnitrosamine* ; Liver* ; Necrosis ; Rats*

The effect of NDMA after oral administration (17 mg/ml) on the glycoconjugates of lingual von Ebner's gland and mucous gland were investigated with lectin histochemical methods. For lectin histochemical studies, the biotinylated lectins (DBA, PNA, SBA, BSL -1, sWGA, RCA -1, LCA, UEA -1, and ConA) were applied. Lectin binding patterns of glycoconjugates of lingual von Ebner's gland showed the decreased affinity for DBA, PNA, BSL -1 and sWGA in NDMA -treated group compared with control group. The remarkable decrease of binding affinity of NDMA -treated group was observed in PNA for 12 and 24 hours, DBA for 96 hours, BSL -1 for 72 hours, and sWGA for 3 hours, while the striking decrease of BSL -1 and sWGA binding was observed in NDMA -treated group for 12 hours. But these decreases of binding were tended to recover in PNA and sWGA after 72 hours of NDMA treatment, and in DBA after 120 hours. The binding affinity of SBA and RCA -1 was decreased in NDMA -treated group for 3 hours, while the other NDMA -treated group showed an increased affinity. Especially, the increase of SBA binding was remarkable. There was a little change in binding affinity of UEA -1, LCA and Con A in NDMA -treated group. Lectin binding patterns of glycoconjugates of lingual mucous gland showed decreased affinities for SBA, sWGA and UEA -1 in NDMA -treated group. The striking decreases of binding affinity for NDMA -treated group was observed in SBA and sWGA for 3 hours, and UEA -1 for 3 and 24 hours. And the remarkable decreases of binding affinity for NDMA -treated group was found in SBA for 24 and 48 hours, sWGA for 48, 72 and 96 hours, and UEA -1 for 48 hours. These decreases of binding affinity of NDMA -treated group were tended to recover in SBA and UEA -1 after 96 hours and in sWGA after 120 hours. The binding affinity for PNA and ConA showed a little but not remarkable increase in NDMA - treated group, and LCA binding showed a little decrease following a little increase in NDMA - treated group. The affinity of DBA binding was decreased in NDMA -treated group for 12 hours and 24 hours, while the other NDMA -treated group showed an increased affinity. Especially, there was a remarkable increase in NDMA -treated group for 96 hours. From these results, it is suggested that the toxicity of NDMA may be related with the carcinogen of the rat tongue, and glycoconjugates are concerned with the repaire of the destruction of the lingual mucous acini.
Administration, Oral ; Animals ; Dimethylnitrosamine* ; Glycoconjugates* ; Lectins ; Rats* ; Salivary Glands* ; Strikes, Employee ; Tongue ; von Ebner Glands

The purpose of this study was to evaluate the influence of high dose carbon tetrachloride (CCI4) on the hepatotoxic effect of dimethylnitrosamine (DMN) which induces acute hemorrhagic necrosis in liver. Rats were injected intraperitoneally DMN dissolved in physiologic saline by a dose of 40 mg/kg. For changes related to CCI⁴ pretreatment, rats were injected intraperitoneally CCI⁴ dissolved in olive oil by a dose of 0.4 mg/kg, and then injected DMN. The livers were extracted from the rats 3, 6, 12, 24, 48, 72, and 120 hours after CCI⁴ and/ or DMN injection. Liver tissues were examined with light and electron microscopes. The results were summarized as follows; Light microscopic findings: Severe centrilobular hemorrhagic necrosis developed from 12 hours after injection of DMN and continued to 120 hours. On injection of DMN after CCI4 pretreatment, Massive necrosis occurred early. But active regenerative changes were produced in 24 hours. In 120 hours, the liver recovered in almost normal appearance. The degree of necrosis in pretreated group was similar to that in DMN injection only, and the time of recovery was faster in pretreated group. Electron microscopic findings: The early change was mainly disorganization of RER in DMN injection, and clumping and vesicular dilatation of ER in injection of CCI4. In pretreatment group, the early change was similar in appearance with CCI4 group, but severer in degree. According to the results, it was revealed that acute toxic effect of DMN was recovered more rapidly in pretreatment group. Thus it was suggested that CCI4 had protective effect in DMN hepatotoxicity.
Animals ; Carbon Tetrachloride* ; Carbon* ; Dilatation ; Dimethylnitrosamine ; Hepatocytes* ; Liver ; Necrosis ; Olive Oil ; Rats

OBJECTIVESTo study the dynamic change of hepatic oval cells (HOC) in the process of rat liver cirrhosis formation induced by dimethylnitrosamine (DMN), and to explore its pathophysiology significance.

METHODSA rat cirrhosis model was established by using DMN. Microscopical and electronmicroscopical changes of HOC were examined. Thy1.1 was detected by immunohistochemical method at different times. The ratio of HOC was checked using image pattern analysis and Western blot. The number of HOC was counted microscopically.

RESULTSAt the 4th week after DMN administration, the liver fibrosis was at its peak, with false lobules formation combined with large areas of hemorrhage and necrosis. The fibrosis started to minimize at the 6th week, and also the inflammatory changes at the 8th week. Thy1.1 positive stained cells dispersed at the 2nd week; increased at the 4th week around fiber septa; reached its peak at the 6th week, then decreased at the 8th week. The results of image pattern analysis, cell counting under light microscope and Western blot were constant, with the highest cell numbers at the 6th week, and dropped at the 8th week. The ultrastructure of HOC was characterized by their small sized, oval nuclei, and higher nucleus/plasma ratio.

CONCLUSIONDuring the formation and reduction of rat cirrhosis caused by DMN, Thy1.1 stained HOC showed notable dynamic change, which may play an important role in the cirrhotic process.

Animals ; Dimethylnitrosamine ; Hepatocytes ; metabolism ; Liver Cirrhosis, Experimental ; metabolism ; Male ; Rats ; Rats, Wistar ; Thy-1 Antigens ; metabolism

OBJECTS: 99mTc-lactosylated human serum albumin (LSA) is a newly synthesized radiopharmaceutical that binds to asialoglycoprotein receptors, which are specifically presented on the hepatocyte membrane. Hepatic uptake and blood clearance of LSA were evaluated in rat with acute hepatic injury induced by dimethylnitrosamine (DMN) and results were compared with corresponding findings of liver enzyme profile and these of histologic changes. MATERIALS AND METHODS: DMN (27 mg/kg) was injected intraperitoneally in Sprague-Dawley rat to induce acute hepatic injury. At 3 (DMN-3), 8 (DMN-8), and 21 (DMN-21) days after injection of DMN, LSA injected intravenously, and dynamic images of the liver and heart were recorded for 30 minutes. Time-activity curves of the heart and liver were generated from regions of interest drawn over liver and heart area. Degree of hepatic uptake and blood clearance of LSA were evaluated with visual interpretation and semiquantitative analysis using parameters (receptor index : LHL3 and index of blood clearance : HH3), analysis of time-activity curve was also performed with curve fitting using Prism program. RESULTS: Visual assessment of LSA images revealed decreased hepatic uptake in DMN treated rat, compared to control group. In semiquantitative analysis, LHL3 was significantly lower in DMN treated rat group than control rat group (DMN-3: 0.842, DMN-8: 0.898, DMN-21: 0.91, Control: 0.96, p< 0.05), whereas HH3 was significantly higher than control rat group (DMN-3: 0.731, DMN-8: 0.654, DMN-21: 0.604, Control: 0.473, p< 0.05). AST and ALT were significantly higher in DMN-3 group than those of control group. Centrilobular necrosis and infiltration of inflammatory cells were most prominent in DMN-3 group, and were decreased over time. CONCLUSION: The degree of hepatic uptake of LSA was inversely correlated with liver transaminase and degree of histologic liver injury in rat with acute hepatic injury.
Animals ; Asialoglycoprotein Receptor ; Dimethylnitrosamine* ; Heart ; Hepatocytes ; Humans ; Liver* ; Membranes ; Necrosis ; Radionuclide Imaging* ; Rats* ; Rats, Sprague-Dawley ; Serum Albumin*

BACKGROUND/AIMS: Hepatic fibrosis is known to be a predisposing condition of cirrhosis for which there is no proven effective therapy. The aim of this study was to investigate the effect of pentoxifylline and ciprofloxacin on biochemical and histological features of rat hepatic fibrosis induced by dimethylnitrosamine (DMN). METHODS: Seventy male Sprague-Dawley rats were divided into four groups including control (n = 10), DMN (n = 20), DMN plus pentoxifylline (n = 20) and DMN plus ciprofloxacin (n = 20). The rats were injected intraperitoneally with normal saline in the control group and the aforementioned chemicals in the study groups three times a week for 3 weeks. Two rats of the control group, and fives of each study group were sacrificed weekly after the beginning of experiment. From sacrified rats the following parameters of hepatic fibrosis were determined: AST, ALT, cytokines IL-1beta, TNF-alpha and INF-gamma, and histological features of hepatic tissue. RESULT: Rat weight, serological and histological findings were distinctively improved in two treated groups compared with untreated DMN group(p<0.05), The antifibrogenic activity between treated groups was rather better in the group treated with pentoxifylline than in the group treated with ciprofloxacin. During the first and second weeks after experiment the distribution of hepatic stellate cells in treated groups was limited, whereas DMN group showed their diffuse distribution. At the third week DMN group displayed micronodular cirrhosis, but treated groups showed only mild centrilobular fibrotic areas without developing cirrhosis. CONCLUSION: Our results indicate that pentoxifylline and cirprofloxacin may be protective against DMN induced rat hepatic fibrogenesis, while accompanying the inhibition of hepatic stellate cells during the early stage of hepatic fibrogenesis.
Animals ; Ciprofloxacin* ; Cytokines ; Dimethylnitrosamine ; Fibrosis* ; Hepatic Stellate Cells ; Humans ; Male ; Pentoxifylline* ; Rats* ; Rats, Sprague-Dawley ; Tumor Necrosis Factor-alpha

OBJECTIVETo investigate the feasibility of real-time elastography for quantitative evaluation of liver fibrosis in a rat model.

METHODSA total of 70 male Wistar rats were included in the group for dimethylnitrosamine (DMN)-induced liver injury, and 10 saline-injected rats were used as normal control. Hepatic injury was induced by a single intraperitoneal injection of DMN at a dose of 50 mg/kg of body weight. Nine or ten rats in the group with DNM injected and one or two rats in the normal control group were randomly selected and sacrificed at each of the following post-injection time: day 5, 7, 10, 14, 21, 24, and 28. And their livers were taken for pathology analysis. All the rats underwent real-time elastography before sacrificed in order to acquire area ratio of low-strain region (% AREA) and liver fibrosis index (LF index) which were compared with the stage of liver fibrosis and grade of necroinflammatory pathologically. By the different data, Spearman correlation analysis, rank-sum test or receiver operating characteristic curve was used.

RESULTSAmong 58 successfully modeled rats, there were nine, 13, 14 and 12 rats of S1, S2, S3 and S4 liver fibrosis on pathology, respectively, which were with or without mild necroinflammatory. The other 10 rats were found to be S0 with severe necroinflammatory. Values of LF index and % AREA both increased with liver fibrosis stage (P less than 0.05). There was certain correlation between LF index and liver fibrosis stage (r=0.643, P=0.000), so was % AREA and liver fibrosis stage (r=0.662, P=0.000). As for LF index, Areas under the receiver operating characteristic curve (Az) was 0.943, 0.890, 0.743 and 0.821 for the diagnosis of hepatic fibrosis S1 or higher, S2 or higher, S3 or higher and S4, respectively; as for % AREA, they were 0.948, 0.883, 0.772 and 0.842, respectively. However, we found a significant difference for LF index or % AREA between S0 with and without severe inflammatory activity rats (P=0.005 and P=0.017).

CONCLUSIONReal-time elastography is available for quantitative assessment of liver fibrosis in rats induced by DMN, but severe inflammatory activity can affect its accuracy.

Animals ; Dimethylnitrosamine ; adverse effects ; Elasticity Imaging Techniques ; Liver ; pathology ; Liver Cirrhosis, Experimental ; chemically induced ; pathology ; Male ; Rats ; Rats, Wistar

Actins ; analysis ; Animals ; Dimethylnitrosamine ; Immunohistochemistry ; Liver ; metabolism ; pathology ; Male ; Necrosis ; chemically induced ; pathology ; Rats ; Rats, Wistar ; Reticulin ; analysis ; Silver Staining

European Medicines Agency withdrew valsartan from European market in July 2018 because it was contaminated with carcinogen, N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA). Medicines and Healthcare Products Regulatory Agency also found the same contamination and withdrew it from England market. US Food and Drug Administration followed the action after confirming its contamination. Ministry of Food and Drug Safety (MFDS) conducted testing all the valsartans at Korean market and withdrew some of them from market after confirming the contamination with NDMA. MFDS provided the pharmaceutical companies and laboratory institutions with the manual for testing both NDMA and NDEA and educated relevant personnels. MFDS also evaluated the health impact of the contaminated valsartan on the hypertensive patients who took the valsartan, which was shown to be very low risk of additional cancer incidence. MFDS pronounced strengthening of the safety management for the raw materials of the medicines. For guaranteeing the safety of medicines, more comprehensive drug safety management system from developing new drugs to consuming the medicines should be established. For achieving such a goal, active participation of all the stakeholders of the medicines including governmental agencies including MFDS and Ministry of Health and Welfare, the National Assembly, healthcare professionals, pharmaceutical companies, mass media, and general population including patients should be needed.
Antihypertensive Agents ; Delivery of Health Care ; Diethylnitrosamine ; Dimethylnitrosamine ; England ; Humans ; Incidence ; Mass Media ; Safety Management ; United States Food and Drug Administration ; Valsartan