1.Effect of Siwu decoction and its combined administration on hepatic P450 enzymatic activity and mRNA expression in rats.
Miao LIANG ; Zeng-Chun MA ; Jian-Feng YI ; Yu-Guang WANG ; Hong-Ling TAN ; Cheng-Rong XIAO ; Qian-De LIANG ; Xiang-Lin TANG ; Hua LI ; Guo-Lin SHEN ; Yue GAO
China Journal of Chinese Materia Medica 2013;38(21):3720-3725
To study the effect of Siwu decoction (SWD) compound and its combined administration on hepatic P450 enzymatic activity and mRNA expression in rats. Rats were orally administered with SWD and water decoction combined with other medicines for two weeks, and then sacrificed. Their livers were perfused with normal saline to prepare liver micrisomes. Mixed probe and liver microsome in vitro incubation method were adopted to detect the effect of SWD on hepatic cytochrome P450. The real-time quantitative polymerase chain reaction (Q-PCR) was used to detect the effect of SWD on the expression of hepatic cytochrome P450. Compared with the control group, the SWD compound group showed higher CYP1A2 enzymatic activity (P < 0.05); Rehmanniae-paeoniae, angelicae-paeoniae, angelicae-rhizome, paeoniae-rhizome groups had lower CYP1A2 and CYP2C19 enzymatic activities (P < 0.05); And the compound group, the single component group and the combination group showed lower CYP2B6 enzymatic activities (P < 0.05). The compound could up-regulated the mRNA expression of CYP2B1 (P < 0.05); And the four single components could down-regulated the mRNA expression of CYP2B1 (P < 0.05). SWD compound had the effect in inducing CYP1A2 enzymatic activity. The rehmanniae-paeoniae group and the angelicae-paeoniae group had identical enzymatic activity with the control group, but significant down-regulation in CYP1A2 enzymatic activity after being combined with paeoniae. The compound and its combined administration showed the inhibitory effect on CYP2B6 enzymatic activity, particularly being combined with angelicae. The compound showed identical effect with the four single components in terms of CYP1A2 mRNA expression and enzymatic activity.
Animals
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Cytochrome P-450 Enzyme System
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genetics
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metabolism
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Drugs, Chinese Herbal
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pharmacology
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Liver
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drug effects
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enzymology
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Microsomes, Liver
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drug effects
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enzymology
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RNA, Messenger
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genetics
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metabolism
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Rats
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Rats, Wistar
2.Effect of thyroid hormone on the alcohol dehydrogenase activities in rat tissues.
Dong Sun KIM ; Chang Beom LEE ; Yong Soo PARK ; You Hern AHN ; Tae Wha KIM ; Choon Suhk KEE ; Ju Seop KANG ; Ae Son OM
Journal of Korean Medical Science 2001;16(3):313-316
The effects of thyroid hormone on hepatic and gastric alcohol dehydrogenase (ADH) activities (nM of NADH/min/mg of cytosolic protein) have been investigated in male Sprague Dawley rats treated with thyroxine (1 mg/kg, po) for 14 days. Whereas hepatic ADH activity in thyroxine-treated rats decreased by 61.3% of control rats (26.4 vs 43.2, p<0.001), gastric ADH activity increased by 262.9% of control rats (4.9 vs 1.9, p<0.001). As for the activities of the lung and kidney, thyroxine treatment did not produce any statistically significant changes. These data suggest that thyrotoxicosis causes a decrease of hepatic alcohol metabolism, and that the increase of gastric ADH activity in thyrotoxic rats can partly restore the first-pass metabolism of ethanol.
Alcohol Dehydrogenase/*metabolism
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Animal
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Gastric Mucosa/enzymology
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Kidney/enzymology
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Liver/drug effects/*enzymology
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Lung/enzymology
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Male
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Rats
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Rats, Sprague-Dawley
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Stomach/drug effects/*enzymology
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Thyrotoxicosis/chemically induced/metabolism
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Thyroxine/administration & dosage/*metabolism/pharmacology
3.Inhibition of 1,3,8-trihydroxy-5-methoxyxanthone on cytochrome P450s.
Wei CAO ; Ya-jie CAO ; Zhe-yi HU ; Qi YU ; Li-qing WANG ; Gui-shan TAN ; Ze-neng CHENG
Journal of Central South University(Medical Sciences) 2006;31(6):858-861
OBJECTIVE:
To explore the inhibitive effects of 1,3,8-trihydroxy-5-methoxyxanthone (TMX) on cytochrome P450s (CYP450s) in human liver microsomes.
METHODS:
Probe drugs were incubated with and without adding TMX to determine the changes of enzyme activities. The concentration ratio of metabolites to probe drugs was used to present enzyme activities. Concentrations of the probe drugs and their metabolites in the incubated mixture were detected by high performance liquid chromatography.
RESULTS:
The variations (mean, 95%CI) of the activities of CYP1A2, CYP2C9, CYP2C19, CYP2E1 and CYP3A4 were 2.95 x 10(-3) (2.03 x 10(-3), 3.88 x 10(-3)), 3.14 x 10(-2) (1.87 x 10(-2), 4.42 x 10(-2)), 2.27 x 10(-3) (-1.4 x 10(-2),1.81 x 10(-2)), 7.72 x 10(-2) (-0.83 x 10(-2), 0.2374), and -0.2548 (-2.9802, 2.4707), respectively. The activities of CYP1A2 and CYP2C9 were significantly reduced in the present of TMX.
CONCLUSION
TMX (10 micromol/L) has significant inhibitive effect on the activities of CYP1A2 and CYP2C9, but no significant inhibitive effect on the activities of CYP2C19, CYP2E1 and CYP3A4.
Cytochrome P-450 Enzyme System
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metabolism
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Humans
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Microsomes, Liver
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drug effects
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enzymology
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Xanthones
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pharmacology
4.Intervention effect of aqueous fractions from Boschniakia rossica on hepatic oxidative stress in mice with liver injury induced by carbon tetrachloride.
Wen-Xi ZHAO ; Mei-Hua JIN ; Tian LI ; Yu-Jiao WANG ; Ji-Shu QUAN
China Journal of Chinese Materia Medica 2013;38(6):875-878
OBJECTIVETo investigate the intervention effect of aqueous fractions from Boschniakia rossica (BRAF) on hepatic oxidative stress in mice with liver injury induced by carbon tetrachloride (CCl4).
METHODThe experimental mice were randomly assigned into the normal control group, the model group, the silymarin (positive control) group, as well as high and low dose BRAF groups. Mice were treated intragastrically with silymarin or BRAF once every day for 7 days. At the end of the experiment, CCl4 was injected intraperitoneally into the mice to establish the acute liver injury model. The pathological changes was detected with hematoxylin and eosin (HE) staining, and the activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), superoxide dismutase (SOD) , catalase (CAT), glutathione peroxidase (GPx), Na+ -K+ -ATPase, Ca2+ -Mg2+ -ATPase, and the contents of reduced glutathione (GSH) and malondialdehyde (MDA) were detected by the colorimetric method.
RESULTBRAF significantly reduced ALT, AST and ALP activities in serum, alleviated hepatic injury induced by CCl4, increased SOD, CAT, GPx and GSH levels in liver, and SOD, Na + -K + -ATPase and Ca2+ -Mg2 + -ATPase activities in liver mitochondria, and decreased the MDA content in liver and liver mitochondria.
CONCLUSIONBRAF reduces hepatic oxidative stress in mice with acute liver injury induced by CCl4, thereby showing the protective effect on mice with acute liver injury induced by CCl4.
Animals ; Carbon Tetrachloride ; toxicity ; Chemical and Drug Induced Liver Injury ; enzymology ; metabolism ; pathology ; Drugs, Chinese Herbal ; chemistry ; pharmacology ; Liver ; drug effects ; enzymology ; metabolism ; pathology ; Male ; Mice ; Mitochondria ; drug effects ; metabolism ; Orobanchaceae ; chemistry ; Oxidative Stress ; drug effects ; Solubility ; Water ; chemistry
5.Effects of xuefu zhuyu decoction on antioxidant and drug-metabolizing enzymes in liver of rats.
Xing-hua FAN ; Wei-Zhou SHI ; Yun-xiang CHENG ; Kai-jie ZOU ; Xiu-fen YANG
China Journal of Chinese Materia Medica 2014;39(22):4453-4458
Xuefu Zhuyu decoction (XFZYD) is a famous traditional Chinese medicine (TCM) formula, is widely used in the treatment of cardiovascular and cerebrovascular diseases in China over one hundred years. But its effect on antioxidant and drug-metabolizing enzymes are unknown. This study was to observe the effects of Xuefu Zhuyu decoction (XFZYD) on the activities of antioxidant and drug metabolism enzymes (DMEs) in liver of rats. Male SD rats, treated with XFZYD at the dosage of 3.51, 7.02 and 14.04 g x kg(-1) per day for 15 days, serum were collected, tissue fluid, cytosols and microsomes isolated from liver tissues were prepared by centrifugation according to the standard procedure, the activities of antioxidant enzymes and drug-Metabolizing Enzymes were determined by UV-V is spectrophotometer. In serum, the activities of AST was not significantly affected by the treatment with XFZYD, at the high- est dose, the levels of ALT, Cr and BUN were significantly decreased (P < 0.05). GPX were significantly increased at the dose of 7.02, 14.04 g x kg(-1) (P < 0.05), CAT were significantly increased at the highest dose (P < 0.05). T-SOD was not significantly af- fected by this treatment. In the liver tissue, GPX was significantly increased at the dose of 3.51, 7.02 g x kg(-1) (P < 0.05), GST, CAT and T-SOD were not significantly affected following this treatment. In cytosols, GST was significantly increased at the dose of 3.51 g x kg(-1) (P < 0.05), T-SOD was remarkable induced at the dose of 3.51 and 7.02 g x kg(-1) (P < 0.05). In microsomes, XFZYD had no significant effect on Cytochromeb5, NADPH-Cytochrome P450 reductase, CYP3A, CYP2E1 and UGT, XFZYD significantly in- duced GST at the dose of 3.51 and 7.02 g x kg(-1) (P < 0.05), and the level of GSH were significantly increased by XFZYD at the dose of 3.51, 7.02 and 14.04 g kg(-1) (P < 0.05). These findings suggest XFZYD can induce the activities of GPX, CAT, SOD, GST and increase GSH level in liver of rats, which indicate XFZYD may have detoxification and antioxidant functions.
Animals
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Antioxidants
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metabolism
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Drugs, Chinese Herbal
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pharmacology
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Inactivation, Metabolic
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drug effects
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Liver
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drug effects
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enzymology
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Male
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Rats
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Rats, Sprague-Dawley
6.Assessment of mitochondrial toxicity induced by zidovudine and adefovir dipivoxil in rats.
Bin ZHU ; Zhen-ni ZHU ; Jun-zhong WANG ; Shun-mei HUANG ; Xue-mei FENG ; An-yi LI ; Dong-liang YANG ; Bao-ju WANG
Chinese Journal of Hepatology 2012;20(10):794-797
OBJECTIVETo explore the mitochondrial toxicities induced by zidovudine (AZT) and adefovir dipivoxil (ADV) antiviral drugs using a rat model system.
METHODSTwelve healthy Sprague-Dawley rats were randomly divided into three equal groups and treated by oral gavage with zidovudine (125 mg/kg/day), adefovir (40 mg/kg/day), or saline (equal volume) for 28 days. The rats' body weights were measured once a week, and blood was collected every two weeks for blood and biochemical tests. All animals were sacrificed at the end of treatment, and liver, kidney, skeletal muscle, and cardiac muscle were collected by necropsy. Mitochondria were isolated from the respective tissue samples, and the activities of respiratory chain complexes were measured. DNA was purified from each sample and the mitochondrial DNA (mtDNA) content was monitored by quantitative real time PCR. Mitochondrial morphology was analyzed under electron microscope.
RESULTSNo significant adverse effects, including body weight loss, abnormal blood or biochemistry, were observed in rats treated with AZT or ADV. The activities of mitochondrial cytochrome c oxidase in liver and cardiac muscle were slightly decreased in rats treated with AZT (liver: 9.44+/-3.09 vs. 17.8+/-12.38, P?=?0.21; cardiac muscle: 32.74+/-5.52 vs. 24.74+/-20.59, P?=?0.28; kidney: 4.42+/-1.53 vs. 14.45+/-13.75, P?=?0.18; skeletal muscle: 33.75+/-8.74 vs. 40.04+/-2.49, P?=?0.45). The mtDNA content was significantly decreased in cardiac muscle of AZT-treated rats (cardiac muscle: 0.15+/-0.13 vs. 0.32+/-0.42, P?=?0.85). The morphology of mitochondria in liver, kidney, skeletal muscle, and cardiac muscle was significantly altered in the AZT-treated rats and included disappearance of the outer membrane, severely damaged structure, and swollen or completely absent cristae. No obvious effects were noted in the ADV- or saline-treated rats.
CONCLUSIONSignificant adverse effects related to mitochondrial toxicity were observed in rats treated with AZT. The slightly decreased mtDNA content in ADV-treated rats may suggest that this antiviral drug can also cause mitochondrial toxic effects.
Adenine ; adverse effects ; analogs & derivatives ; Animals ; DNA, Mitochondrial ; drug effects ; Electron Transport Complex IV ; metabolism ; Female ; Kidney ; enzymology ; Liver ; enzymology ; Mitochondria ; drug effects ; metabolism ; Mitochondria, Heart ; drug effects ; Mitochondria, Liver ; drug effects ; Mitochondria, Muscle ; drug effects ; Muscle, Skeletal ; enzymology ; Myocardium ; enzymology ; Organophosphonates ; adverse effects ; Rats ; Rats, Sprague-Dawley ; Zidovudine ; adverse effects
7.Induction of rat hepatic cytochrome P-450 3A by zolmitriptan mediated with pregnane X receptor.
Feng XING ; Lu-Shan YU ; Su ZENG
Journal of Zhejiang University. Medical sciences 2009;38(3):249-254
OBJECTIVETo investigate whether pregnane X receptor (PXR) is involved in the induction of rat hepatic cytochrome P450 3A1/2 by zolmitriptan.
METHODSThe induction effects of zolmitriptan were investigated in three concentrations (100 micromol L(-1)), 50 micromolL(-1)) and 10 micromol L(-1))) using luciferase report gene method based on PXR. Pregnenolone-16 alpha-carbonitrile (PCN) was used as the positive control and the solvent DMSO as the negative control.
RESULTCompared with the negative groups, the positive and high level zolmitriptan groups exhibited a significant induction effect on CYP 3A1, the activity increased to 1.93 and 1.96 times, respectively (P<0.05). The positive, middle level and low level zolmitriptan groups exhibited a significant induction effect on CYP 3A2, the activity increase to 2.51, 2.10 and 1.63 times, respectively (P<0.01, <0.05 ).
CONCLUSIONZolmitriptan can significantly induce CYP 3A2 in low and middle concentrations and induce CYP 3A1 in high concentration.PXR is involved in the induction of CYP 3A1/2 by zolmitriptan.
Animals ; Cytochrome P-450 CYP3A ; drug effects ; metabolism ; Liver ; enzymology ; metabolism ; Oxazolidinones ; pharmacology ; Rats ; Receptors, Steroid ; metabolism ; physiology ; Tryptamines ; pharmacology
8.Reverse effect of Yinchenhao decoction in dimethyl nitrosamine-induced hepatic fibrosis in rats.
Yong-Hong WANG ; Chen-Xi ZHAO ; Ben-Mei CHEN ; Min HE ; Lin-Qi LIU ; Chun-Yan LI ; Xin CHEN
China Journal of Chinese Materia Medica 2014;39(8):1473-1478
OBJECTIVETo discuss the reverse effect of Yinchenhao decoction(YCHD) in dimethyl nitrosamine (DMN)-induced hepatic fibrosis in rats.
METHODThe rat hepatic fibrosis model was established through the intraperitoneal injection with 1% dimethyl nitrosamine (DMN) with a dose of 1.0 mL x kg(-1) x d(-1) for consecutively three weeks, once for the first three days of each. The rats were randomly divided into six groups: the silymarin positive control group (50.0 mg x kg(-1) x d(-1), YCHD high (20.0 g x kg(-1) d(-1)), middle (8.0 g x kg(-1) x d(-1)) and low (3.2 g x kg(-1) x d(-1)) dose groups, the model group and the normal control group. The model group and the normal control group were orally administered with normal saline for consecutively five weeks. The pathologic changes in liver tissues were observed by HE staining. The levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), g-glutamyltransferase (g-GGT), hyaluronic acid (HA), laminin (LN), collagen type IV (CIV) and type III procollagen amino terminal peptide (PIIINP) in serum were determined. The metabolite profiling of amino acid and the content of hydroxyproline in liver tissues were also measured.
RESULTCompared with the model group, YCHD high and middle dose groups could significantly reverse the pathologic changes in liver tissues of rats. YCHD could reduce the levels of ALT, AST, gamma-GGT, HA, LN, CIV, PIIINP in serum and the content of hydroxyproline in liver tissues in a dose-dependent manner, and altered the metabolite profiling of amino acid in rat liver tissues.
CONCLUSIONYCHD has the effect in reversing dimethyl nitrosamine induced hepatic fibrosis in rats.
Alanine Transaminase ; metabolism ; Animals ; Aspartate Aminotransferases ; metabolism ; Collagen Type IV ; metabolism ; Dimethylnitrosamine ; adverse effects ; Drugs, Chinese Herbal ; administration & dosage ; Humans ; Hydroxyproline ; metabolism ; Liver ; drug effects ; enzymology ; metabolism ; Liver Cirrhosis ; chemically induced ; drug therapy ; enzymology ; Male ; Rats ; Rats, Sprague-Dawley
9.Effect of Jiawei Foshou San and its compatibility on hepatic P450 enzyme activity and hepatocyte morphology in rats.
Fang-hong SHANG ; Shan FENG ; Fei-yan ZHANG ; Qian CHEN ; Xian-jin CHEN ; Ji-fen ZHANG ; Xiao-yu XU
China Journal of Chinese Materia Medica 2015;40(10):2030-2036
To investigate the effect of Jiawei Foshou San and its various combined administration on hepatic P450 enzyme activity and hepatocyte morphology in rats. Rats were orally administered with drugs for four weeks and then sacrificed to prepare liver microsomes. The liver microsomes were incubated with the cocktail method; The metabolites were determined with the rapid liquid chromatography with tandem mass spectrometry (LC-MS/MS) to investigate the hepatocyte P450 enzyme activity. In addition, the hepatic pathological changes were observed by using the hematoxylin and eosin (HE) staining. Compared with the control group, the enzyme activity of CYP1A2 and CYP3A4 in the Jiawei Foshou san group showed a significant rise (P < 0.05); the enzyme activity of CYP1A2, CYP2C9, CYP2D6, CYP2E1 and CYP3A4 in the ferulic acid + ligustrazine group and the ligustrazine + tetrahydropalmatine group showed a significant rise (P < 0.05) ; the enzyme activity of CYP1A2, CYP2D6 and CYP2E1 in the ligustrazine group showed a significant rise (P < 0.05); the enzyme activity of CYP3A4 in the ferulic acid group showed a significant reduction (P < 0.05). After the administration with various drugs, the hepatocyte morphologies in the ferulic acid group and the ligustrazine group were normal. The pathological changes were observed in the tetrahydropalmatine group, such as unclear boundary of hepatic lobules, disordered hepatic cell arrangement, blurred edge, anisokaryosis and infiltration of inflammatory cells. The ferulic acid + tetrahydropalmatine group, the ligustrazine + tetrahydropalmatine group and the Jiawei Foshou San group also showed inflammatory infiltration, but with less pathological changes, particularly the Jiawei Foshou San group. The study result shows that Jiawei Foshou San can induce the enzyme activity of CYP1A2 and CYP3A4, and ligustrazine may be the effective substance for inducing CYP1A2. Its combination with ferulic acid and ligustrazine can significantly reduce the liver toxicity of tetrahydropalmatine.
Animals
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Cytochrome P-450 Enzyme System
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metabolism
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Drugs, Chinese Herbal
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administration & dosage
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Female
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Hepatocytes
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drug effects
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enzymology
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Microsomes, Liver
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drug effects
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enzymology
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Rats
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Rats, Sprague-Dawley
10.Glucose-6-phosphatase Activity and Ultrastructures in Hepatocytes of Thioacetamide-treated Mice.
Tai Sun SHIN ; Yong Kun DEUNG ; Soo Sung KIM
Yonsei Medical Journal 1976;17(2):85-96
To investigate the earlier cellular alterations(Glucose-6-Pase activity and morphologic features) caused by a hepatotoxin, thioacetamide (TAA), a single dose of the agent (200mg per kg of body weight) was given intraperitoneally to mice, which were sacrificed at intervals of 4, 8 or 16 hours after corresponding treatments. For histochemical study of glucose-6-phosphatase (G6Pase) activity, unfixed frozen sections were incubation of the Wachstein and Meisel medium and stained. The smallest pieces of liver tissue were fixed in glutaraldehyde and osmic acid, and stained by the routine electron-microscopic techniques. Some pieces of liver were fixed in 10% formalin, embedded in paraffin, and stained with hematoxylin and eosin. There was a rapid and progressive loss of G6Pase activity, in an orderly time sequence, in the experimental group. There were also morphologic changes: loss of cytoplasmic basophilia, cell infiltration and necrosis in the centrilobular and intermediate zones, and an increase of sER, small vesicles and ribosomes in the cytoplasm of hepatocytes, the marked changes of nuclei and nucleoli, and a slight increase of lipid droplets in the cytoplasm at 16 hours after intoxication. The correlation between these cellular alterations was discussed in view of mechanisms in the hepatotoxic action.
Acetamides/adverse effects*
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Animal
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Glucose-6-Phosphatase/metabolism*
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Liver/drug effects*
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Liver/enzymology
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Liver/ultrastructure
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Male
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Mice
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Thioacetamide/adverse effects*
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MH -
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Substances:
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Acetamides
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Thioacetamide
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Glucose-6-Phosphatase