• Molecular & Cellular Toxicology
• /
• v.2 no.1
• /
• pp.48-53
• /
• 2006

[ ${\alpha}-Naphthylisothiocyanate$ ] (ANIT) induces intrahepatic cholestasis, involving damage to biliary epitheial cells. This study investigates hepatic gene expression and histopathological alterations in response to ANIT treatment in order to elucidate early time response of ANIT-induced hepatotoxicity. ANIT was treated with single dose (3, 6, and 60 mg/kg) in corn oil by oral gavage. Serum biochemical and histopathological observation were performed for evaluation of hepatotoxicity level. Affymetrix oligo DNA chips were used for gene expression profile by ANIT-induced hetpatoxicity. Hepatic enzyme levels (ALT, AST, and ALP) were increased in 24 hr high dose group. In microscopic observations, moderate hepatocellular necrosis, were confirmed 24 hr high dose groups. We found that gene expression patterns were dependent on time and dose. Our selected genes were related inflammation and immunomodulation. In this study, ANIT-induced hepatotoxicity was involved in acute phase responses and provides evidence for role of neutrophil could be mechanism associated with ANIT-mediated hepatotoxicity.

• Korean Journal of Veterinary Research
• /
• v.35 no.3
• /
• pp.489-496
• /
• 1995

Artemisia messes-schmidiana var viridis(Compositae) has been used for jaundice, hepatitis, diuretic and liver cirrhosis etc. 1-naphthylisothiocyanate(ANIT) has been used as a model compound to study mechanisms of intrahepatic cholestasis in laboratory animals as rat and mouse. The purposes of present study are to examine pharmacological effects of Artemisia messes-schmidiana var viridis water extract(AMWE) on alterations of triacylglycerol, cholesterol, protein, albumin and A/G ratio levels in serum, of histopathological appearances of liver, and that of hepatic microsomal cytochrome P-450 contents. Increased serum triacylglycerol levels by ANIT were significantly decreased with AMWE. However, AMWE posttreatment aggravated ANIT-induced cholesterol increase. Serum total protein and albumin contents, and A/G ratio were decreased in all ANIT-treated groups, and there were increased compared with control by AMWE posttreatment. Hepatic microsomal cytochrome P-450 contents were decreased in either AMWE and ANIT treatment, which greatly increased with AMWE pretreatment. On the other hand, in histological findings, our results shown that ANIT induced increase of lipid droplets and widening of sinusoidal capillary and these phenomena were disappeared with AMWE treatment. In conclusion, AMWE have choleresis effect. Also, AMWE improved lipid metabolism, protection and regeneration of hepatocytes in ANIT-induced cholestasis.

• Korean Journal of Veterinary Research
• /
• v.35 no.3
• /
• pp.481-488
• /
• 1995

In oriental folk medicine, Artemisia messes-schmidiana var viridis(Compositae) has been used for jaundice, hepatitis, diuretic and liver cirrhosis etc. 1-naphthylisothiocyanate(ANIT) has been used for more than 20 years as a model compound to study mechanisms of intrahepatic cholestasis in laboratory animals as rat and mouse. Various biochemical and morphological changes including biliary epithelial and parenchymal cell necrosis occur in the liver of animals treated with ANIT. The purposes of present study are to examine pharmacological effects of Artemisia messes-schmidiana var viridis water extract(AMWE) on alterations of secretion volume and total bile acids level in bile juice, and that of serum AST, ALT, ALP, bilirubin, and glucose levels in rat. AMWE stimulated bile secretion and recovered ANIT-induced cholestasis. Bile acid concentrations increased to more than 60% compared with normal by ANIT, which were returned toward normal value with AMWE treatment. Serum AST and ALT activities were increased by ANIT and yet which were significantly decreased with AMWE treatment. In addition, this effect was apparent in AMWE pretreatment group. Serum glucose levels were increased with AMWE and ANIT, while were decreased compared with control in AMWE posttreatment group. Increased serum total bilirubin contents and ALP activities by ANIT were significantly decreased with AMWE posttreatment. In conclusion, AMWE exerted bile acid-independent choleresis effect and then improved to normal conditions ANIT-induced cholestatic syndromes. Also, AMWE have protective and regenerative effect of hepatocytes in rat.

• Proceedings of the PSK Conference
• /
• 2003.10b
• /
• pp.214.1-214.1
• /
• 2003

Metabonomic analysis using Liquid Chromatography-Mass Spectrometry (LC-MS) was employed to test the feasibility to predict chemical-induced toxicity. Time-dependent metabolic variations were evaluated in rats treated with the model hepatotoxin, ${\alpha}$- naphthylisothiocyanate (ANIT). Urine samples of ANIT treated group and control group were collected up to 7 days postdose. Urine samples were analyzed by gradient HPLC combined with electrospray mass spectrometry. The chromatographic results were data-reduced and analyzed using principal component analysis to show the time dependent biochemical variations induced by ANIT toxicity. (omitted)

• Journal of Veterinary Clinics
• /
• v.7 no.1
• /
• pp.381-390
• /
• 1990

In order to study the effects of administration of carbon tetrachloride(CCI$_4$) and 1-naphthylisothiocyanate(ANIT) on the liver of Korean black goats, some liver function tests and liver biopsy were done on 4 Korean black goats dosed with CCI$_4$(0.4m1/kg of body weight) in-traruminally and 4 Korean black goats dosed with ANIT(400mg/kg of body weight) by stomach tube. BSP Tl/2 and serum total bilirubin concentration in goats dosed with CCI$_4$ were increased gradually, reached to maximum value on 2nd and 1st day, respectively, and then began to decrease in normal range, gradually. In goats dosed with ANIT, BSP Tl/2 and serum total bilirubin concentration were increased rapidly, reached to maximum value on 0.5 and 1st day, respectively, and then returned to normal ragne, rapidly. Serum SDH, AST and GGT activities in goats dosed with CCI$_4$ were increased rapidly and reached to maximum value on 3rd, 1st and 2nd day, respectively. Thereafter, the serum enzyme activities began to decrease in normal range gradually. In goats dosed with ANIT, however, serum SDH, AST and GGT activities were not changed. The histopathologic changes in goats dosed with CCI$_4$ were lipidosis and centrilobular nee-rosis of the hepatic parenchyma. In goats dosed with ANIT, hyperplasia of bile duct epithelium was noticeable, but pathologic changes in liver parenchyma were not noticed. Conclusively, in Korean black goats dosed with CCI$_4$, main finding was necrosis of hepatic parenchyma. In Korean black goats dosed with ANIT, main finding was cholestasis.

• The Journal of Korean Medicine
• /
• v.17 no.2 s.32
• /
• pp.214-226
• /
• 1996

In an attempt to evaluate the effect of high and low concentration of Injinsaryungsan and high and low concentration of Sosihotang on cholestatic liver injery induced by $ANIT({\alpha}-naphthylisothiocyanate)$, biochemical changes in serum transaminase(GOT, GPT), alkaline phosphate, lactate dehydrogenase, total cholesterol, triglyceride, total-bilirubine were studied and the following results were obtained. 1. High concentration of Injinsaryungsan(2.2g／Kg) inhibited significantly the activity increases of GOT, GPT, ALP, LDH, TC, TG, T-Bilirubine induced by $ANIT({\alpha}-naphthylisothiocyanate)$. 2. Low concentration of Injinsaryungsan(1.1g／Kg) inhibited the activity increases of ALP, LDH, TC, TG with statistical significance, while inhibited the activity increase of GOT ,but with no statistical significance. 3. High concentration of Sosihotang(2.4g／Kg) inhibited the activity increases of LDH, TG, TC with statistical significance while inhibited the activity increases of GOT, GPT, ALP, T-bilirubine with no significance. 4. Low concentration of Sosihotang(1.2g／Kg) inhibited the activity increase of TG, while inhibited the activity increase of ALP, TC with no statistical sig-nificance, but didn't inhibite the activity increases of GOT, GPT, LDH, T-Bil. These results suggest that Injinsaryungsan has more significant effect on the liver injury induced by $ANIT({\alpha}-naphthylisothiocyanate)$ compared with Sosihotang and so can be applicable clinically to virus hepatitis and cholestatic liver injury. Further study will be required to evaluate the effect of Sosibotang on cholangitis and cholecystitis.

• Proceedings of the Korean Society of Toxicology Conference
• /
• 2005.05a
• /
• pp.123-124
• /
• 2005

• Biomolecules & Therapeutics
• /
• v.16 no.3
• /
• pp.203-209
• /
• 2008

The aim of this study was to investigate the hepatoprotective effect of $ACTIValoe^{(R)}$ N-931 complex, a mixture of Aloe vera and Silybum marianum, against acute liver injuries. Acute liver damages were induced by intraperitoneal injection of galactosamine (GalN, 700 mg/kg), naphthylisothiocyanate (ANIT, 40 mg/kg) and ethionine (500 mg/kg). $ACTIValoe^{(R)}$ N-931 (85, 170 and 340) was administered orally 48 h, 24 h, 2 h before and 6 h after the injection of hepatotoxins. At 24 h after GalN treatment the levels of serum aminotransferases and hepatic lipid peroxidation were significantly elevated, whereas hepatic glutathione, serum triglyceride (TG) and total cholesterol were decreased. These changes were attenuated by $ACTIValoe^{(R)}$ N-931 complex. The serum aminotransferase activities and total bilirubin significantly increased at 48 h after ANIT treatment, but were attenuated by $ACTIValoe^{(R)}$ N-931 complex. The bile flow was lower after ANIT treatment, which was restored by $ACTIValoe^{(R)}$ N-931 complex. $ACTIValoe^{(R)}$ N-931 complex reduced the ethionine-induced elevated hepatic TG contents. Histopathological analysis revealed that signs of liver injury were prominent at 24 h as result of ethionine injection, demonstrated by extensive areas of fatty change and microvesicular steatosis were observed around cells. These changes were attenuated by $ACTIValoe^{(R)}$ N-931 complex. Our results suggest that the $ACTIValoe^{(R)}$ N-931 complex has a protective effect on acute liver injury.

• Proceedings of the Korean Society of Applied Pharmacology
• /
• 1996.04a
• /
• pp.199-199
• /
• 1996

급성 간질환모델에 대한 인진호 추출분획의 간장 약효검색, 방법 1. $CCl_4$ 간장해 : SD계 수컷 흰쥐에 $CCl_4$와 olive oil 혼합액(1:4v/v%)을 체중100g당 0.2$m\ell$씩 복강내 투여하였으며, 시험약물은 $CCl_4$ 혼합액 투여 4시간전 및 6시간후에 경구로 2회 투여하였다. 48시간후에 부검하여 혈청을 얻어 간기능검사 항목인 ALT 및 AST 활성을 측정하였다. 2. D-Galactosamine 간염 : SD계 수컷 흰쥐에 D-GalactosamineㆍHCl을 650mg/kg씩 복강내 투여하였으며, 시험약물은 $CCl_4$ 간장해시험과 동일하게 2회 경구투여하였다. D-Galactosamine 투여 24시간 후에 부검하여 혈청을 얻어 간기능검사 항목인 ALT 및 AST 활성을 측정하였다. 3. 담즙울체모델 : SD계 수컷 흰쥐에 ANIT 100mg을 olive oil 1$m\ell$에 현탁시켜 80$m\ell$/kg b.wt. 용량으로 1회 경구투여하였으며, 시험약물은 ANIT 투여전 2시간, 투여 후 6, 22, 28시간 간격으로 4회 경구투여하였다. ANIT 투여 47시간 후에 1시간 동안 담즙을 채취하였고, ANIT 투여 48시간째 채혈하여 혈청내 총빌리루빈치를 측정하였으며 담즙배출량, 담즙중 담즙산량도 측정하였다. 4. 약물투여 음성대조 : 1% CMC-Na 용액(10$m\ell$/kg b.wt.) 양성대조 : Silymarin(25mg/kg), UDCA(25mg/kg), DDB(37.5mg/kg) 인진호추출분획 : 인진호 원료의 수침액인 BE분획의 수득률을 기준으로 하여, KP(180mg/kg), PS-1 및 PS-2(300mg/kg), EE(500mg/kg), HH(640mg/kg), BE(1500mg/kg)

• Biomolecules & Therapeutics
• /
• v.2 no.1
• /
• pp.47-53
• /
• 1994

The methylation response as well as the level of methyl donor substance, 5-adenosyl-L-methionine (SAM) has been suggested to be related to hepatotoxicity including hepatocarcinogenesis. But direct correlation between protein methylation and hepatotoxicity has not been established to the present. To observe relationship between protein methylation and short-term hepatotoxicity induced by chemical substances, the activities of protein methylase I and II (PM I, PM II) were examined in cytosolic fraction of SD rat treated orally with acetaminophen(AA), $\alpha$-naphtyl-isothiocyanate (ANIT) and tetracycline (TC) that was known to produce necrosis, cholestasis and steatosis respectively. To evaluate the degree of hepatotoxicity induced by each chemicals, we observed the serum levels of indicative parameters and histopathological alteration. In AA treated group, the activities of PM I were increased at 6, 12 hours after administration, prior to the appearance of the hepatotoxicity by clinical parameters. It was suggested that the levels of PM I were related with the initial stage of hepatotoxic mechanism induced by AA. In ANIT treated group, though most of clinical parameters were significantly increased at 24, 48 hours after administration, the activity of PM I was not changed, indicating that ANIT induced hepatotoxicity was not coupled to protein methylation.