• Korean Journal of Clinical Pharmacy
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• v.9 no.1
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• pp.55-61
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• 1999

The object of this work was to study the pharmacokinetic differences and the cause of these differences in cirrhotic rats induced by N,N-dimethylnitrosamine or carbon tetrachloride treatment when aminophylline (8 mg/kg as theophylline, i.v.) was injected. The concentrations of theophylline and its major metabolite (1,3-dimethyluric acid) in plasma were determined by HPLC. In addition, formation of 1,3-dimethyluric acid from theophylline in microsomes was determined. In cirrhotic rats, the systemic clearance of theophylline was reduced to $17\%$ of the control value while AUC (area under the plasma concentration-time curve) and $(t_{1/2})_{\beta}$ were increased to about 6 fold and 10 fold, respectively. The formation of 1,3-dimethyluric acid was decreased to $33-41\%$ of the control value in microsomes of cirrhotic rat liver. From these results, it can be concluded that in cirrhotic rats induced by N,N-dimethylnitrosamine or carbon tetrachloride the total body clearance of theophylline is markedly reduced due to a reduced hepatic metabolism.

• Environmental Analysis Health and Toxicology
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• v.20 no.3 s.50
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• pp.237-242
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• 2005

This study il focused on the hepatopreventive effect in cirrhotic rats induced by N, N -dimethylnitrosamine treatment when organir Lulfur -containing compoundE were orally injected. Biochemical parameters (aspatate transaminase (AST), alanine transaminase (ALT) alkaline phosphatase (ALP), 1-protein and t-bilirubin) were measured in serum injured liver tissue. The increased AST and ALT values were significantly reduced by organic sulfur-containing compounds at the oral dotes of 50 mg/kg. The result of morphological changes have illustrated the accumulation of liver damages, Each as inflammatory cell accumulation and cirrhosis, caused by N, N-dimethylnitrosamine. Also, it was found that liver damages were prevented by the treatment of organic sulfur- containing compounds.

• YAKHAK HOEJI
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• v.30 no.1
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• pp.8-13
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• 1986

It has been assumed that nitrite, one of the precursor of N-nitrosamine, in human saliva must have been formed from salivary nitrate through the action of microorganism in the oral cavity. In this paper, we have tested the concentration of nitrite and nitrate in human saliva and the degrees of nitrate reduction by oral microflora and identified some bacteria which were able to reduce nitrate. The concentration of nitrite and nitrate was 1.7~9.5ppm and 9.0~28.5ppm respectively. The numbers of total bacteria and nitrate reducing bacteria in four korean human saliva sample were 15~63${\times}10^8$ CFU and 1.0~6.0${\times}10^8$ CFU and the main nitrate reducing bacteria were Streptococcus uberis which was presented in large quantities and showed remarkable reductive activity. Lastly, we knowed that N-dimethylnitrosamine was formed by the reaction between dimethylamine and nitrite in the presence of St. uberis in vitro.

• YAKHAK HOEJI
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• v.35 no.6
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• pp.522-529
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• 1991

The purpose of this research is to evaluate effects of chloramphenicol, phenobarbital and progesterone on damage of DNA, RNA and protein which was induced by dimethylnitrosamine. $N,N-Di[^{14}C]$ methyl-nitrosamine (DMN) was used as a damaging agent and levels of DNA, RNA and protein damage in liver, brain and pancreas were compared with a control group. Pretreatment of mice with chloramphenicol increased protein damage in pancreas two times more than the control level. Liver RNA damage was increased up to 5.8 times and brain DNA damage up to 6.95 times by treatment of phenobarbital but brain RNA damage was decreased significantly down to 21% of the control group. The damage of liver RNA was significantly decreased by treatment of progesterone, although liver protein damage, pancreas RNA damage and pancreas protein damage were increased.

• YAKHAK HOEJI
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• v.41 no.5
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• pp.622-628
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• 1997

Hepatic cirrhosis is a common response to chronic liver injury from many causes and is one of the most common cause of all deaths. This study was carried out to compare experimental hepatic cirrhosis in rats to understand this disease and to apply for the pharmacokinetics in disease state. Following three kinds of experimental models were induced; 1) Bile duct ligation/scission (BDL/S), 2) N, N-dimethylnitrosamine(DMN), 3) Carbon tetrachloride. The hepatic cirrhosis was characterized by examing the liver/body weight ratio, serum biochemical values, hydroxyproline content in liver and histopathological lesions in cirrhotic rat liver. The results are as follows : (1) In BDL/S, the liver was enlarged to 250% of normal liver. In contrast the liver was shrinked to 48% and 78% of the normal liver in DMN and carbon tetrachloride, respectively. (2) In carbon tetrachloride and BDL/S, the serum ALT, AST, ALP and total bilirubin levels were significantly increased to 200~300% of normal level, while ALT and total bilirubin levels were significantly increased in DMN group. (3) Hydroxyproline content in cirrhotic rat liver was significantly 200~500% higher than that of normal liver. (4) Nodular formation with fibrosis was observed in BDL/S, DMN, carbon tetrachloride induced cirrhotic rat liver.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.1
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• pp.87-90
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• 2012

Cholangiocarcinoma (CCA) is the most common cancer in northeastern Thailand. At present, effective diagnosis of CCA either in humans or animals is not available. Monitoring the development and progression of CCA in animal models is essential for research and development of new promising chemotherapeutics. Ultrasonography has been widely used for screening of bile duct obstruction in CCA patients. In this study, we preliminarily investigated the applicability of ultrasonography to monitor the development and progression of CCA in Syrian golden hamsters (n=8) induced by Opisthorchis viverrini (OV)/dimethylnitrosamine (DMN) administration. Ultrasonography and histopathological examination of hamsters was performed at week 0, 20, 24 and 28 of OV infection or at the start of water/Tween-80 administration to controls. The ultrasonographic images of liver parenchyma and gallbladders of OV/DMN-induced CCA hamsters showed sediments in gallbladder, thickening of gallbladder wall, and hypoechogenicity of liver parenchyma cells. The ultrasonographic images of liver tissues were found to correlate well with histopathological examination. Although ultrasonography does not directly detect the occurrence of CCA, it reflects the thickening of bile ducts and abnormality of liver tissues. It may be applied as a reliable tool for monitoring the development and progression of CCA in animal models in research and development of new promising chemotherapeutics for CCA.

• Preventive Nutrition and Food Science
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• v.1 no.2
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• pp.151-158
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• 1996

Antimutagenic effect of Doenjang (Korean soy paste) on various carcinogens in Salmonella typhimurium strains of TA98 and TA100 were studied. By the addition of methanol extract of Doenjang to aflatoxin B₁(AFB₁)in the experimental system, the mutagenicity of AFB₁ on the strains of TA98 and TA100 was com-pletely inhibited. The methenol extract of the Doenjang also inhibited the mutagencities induced by direct mutagens such as N-methy1-N'-nitro-N-nitroguanidine(MNNG)and 4-nitroquinoline-1-oxide(4-NQO), and another indirect mutagens of benzo(a) pyrene(BaP) and dimethylnitrosamine(DMN). From the solvents and thin layer chromatographic(TLC) fractionations, free fatty acid(s), especially linoleic acid in Doenjang seemed to be one of the active antimutagenic compounds.

• Korean Journal of Fisheries and Aquatic Sciences
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• v.9 no.4
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• pp.223-231
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• 1976

Dimethylamine(DMA) is known as an origin compound of dimethylnitrosamine which is responsible for carcinogenesis. It has been also reported that relatively large amount of DMA is distributed in fish muscle, particularly in salted and fermented fish. Tn this experiment, the degradation products of protein and trimethylaminoxide(TMAO) by the temperature conditions of $17^{\circ}C\;and\;27^{\circ}C$ in the course of anchovy fermentation with $22\%$ of salt were analysed, and the formation of DMA was discussed. Protein-N decreased through the whole fermentation period ill the conditions of $17^{\circ}C\;and\;27^{\circ}C$ whereas amino-N increased proportionally to the decrease of protein-N, and the increasing rate of amino-N was remarkably faster at $27^{\circ}C$ than at $17^{\circ}C$. Trimethylamine(TMA) gradually increased with the decrease of TMAO till 69th day of fermentation, hereafter tended to slightly decrease. It seemed that the difference in fermentation temperature affects on the formation of DMA and obviously on the variation of TMAO. Both DMA and TMA content were inversely varied with the TMAO content. Correlation coefficient of DMA to TMAO in quantitative variation was shown -0.811 at $17^{\circ}C$ and -0.865 at $27^{\circ}C$ of fermentation temperature respectively. The results suggested that the formation of DMA during fermentation of anchovy was attributed to the degradation of TMAO showing, contributorial ratio of 0.66 at $17^{\circ}C$ and 0.75 at $27^{\circ}C$ respectively.

• Biomolecules & Therapeutics
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• v.28 no.6
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• pp.527-536
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• 2020

Liver fibrosis constitutes a significant health problem worldwide due to its rapidly increasing prevalence and the absence of specific and effective treatments. Growing evidence suggests that apoptosis-signal regulating kinase 1 (ASK1) is activated in oxidative stress, which causes hepatic inflammation and apoptosis, leading to liver fibrogenesis through a mitogen-activated protein kinase (MAPK) downstream signals. In this study, we investigated whether selonsertib, a selective inhibitor of ASK1, shows therapeutic efficacy for liver fibrosis, and elucidated its mechanism of action in vivo and in vitro. As a result, selonsertib strongly suppressed the growth and proliferation of hepatic stellate cells (HSCs) and induced apoptosis by increasing Annexin V and TUNEL-positive cells. We also observed that selonsertib inhibited the ASK1/MAPK pathway, including p38 and c-Jun N-terminal kinase (JNK) in HSCs. Interestingly, dimethylnitrosamine (DMN)-induced liver fibrosis was significantly alleviated by selonsertib treatment in rats. Furthermore, selonsertib reduced collagen deposition and the expression of extracellular components such as α-smooth muscle actin (α-SMA), fibronectin, and collagen type I in vitro and in vivo. Taken together, selonsertib suppressed fibrotic response such as HSC proliferation and extracellular matrix components by blocking the ASK1/MAPK pathway. Therefore, we suggest that selonsertib may be an effective therapeutic drug for ameliorating liver fibrosis.