Differential alteration of cytochrome P450 isoenzymes in two experimental models of cirrhosis

2000 ◽  
Vol 78 (11) ◽  
pp. 912-919 ◽  
Author(s):  
Marie-Claude Bastien ◽  
François Leblond ◽  
Vincent Pichette ◽  
Jean-Pierre Villeneuve
Keyword(s):  
Cytochrome P450 ◽  
Carbon Tetrachloride ◽  
Bile Duct ◽  
Serum Albumin ◽  
Breath Test ◽  
Bile Duct Ligation ◽  
Biliary Cirrhosis ◽  
Breath Tests ◽  
Duct Ligation

Liver diseases are associated with a decrease in hepatic drug elimination, but there is evidence that cirrhosis does not result in uniform changes of cytochrome P450 (CYP) isoenzymes. The objective of this study was to determine the content and activity of four CYP isoenzymes in the bile duct ligation and carbon tetrachloride (CCl4)-induced models of cirrhosis. The hepatic content of CYP1A, CYP2C, CYP2E1, and CYP3A was measured by Western blot analysis. CYP activity in vivo was evaluated with breath tests using substrates specific for different isoenzymes: caffeine (CYP1A2), aminopyrine (CYP2C11), nitrosodimethylamine (CYP2E1), and erythromycin (CYP3A). Bile duct ligation resulted in biliary cirrhosis; CYP1A, CYP2C and CYP3A content was decreased and the caffeine, aminopyrine, and erythromycin breath tests were reduced whereas CYP2E1 content and the nitrosodimethylamine breath test were unchanged compared with controls. CCl4 treatment resulted in cirrhosis of varying severity as assessed from the decrease in liver weight and serum albumin. In rats with mild cirrhosis, CYP content was comparable with controls except for a decrease in CYP2C. The activity of CYPs was also unchanged except for an increase in CYP2E1 activity. In rats with more severe cirrhosis, the content of all four CYP isoenzymes and the caffeine, aminopyrine, and erythromycin breath tests were reduced whereas the nitrosodimethylamine breath test was unchanged. In both models of cirrhosis, there was a significant correlation between the breath tests results and the severity of cirrhosis as assessed from serum albumin levels. These results indicate that content and the catalytic activity of individual CYP enzymes are differentially altered by cirrhosis in the rat and also suggest that drug probes could be useful to assess hepatic functional reserve.Key words: breath test, cirrhosis, cytochrome P450, bile duct ligation, carbon tetrachloride.

Regulation of inducible nitric oxide synthase and nitric oxide during hepatic injury and fibrogenesis

1997 ◽  
Vol 273 (1) ◽  
pp. G124-G130 ◽  
Author(s):  
D. C. Rockey ◽  
J. J. Chung
Keyword(s):  
Nitric Oxide ◽  
Carbon Tetrachloride ◽  
Bile Duct ◽  
Kupffer Cells ◽  
Hepatic Injury ◽  
Bile Duct Ligation ◽  
Inos Mrna ◽  
No Production ◽  
Nonparenchymal Cells ◽  
Duct Ligation

Nitric oxide (NO) production via inducible NO synthase (iNOS) is prominent in the liver after stimulation with cytokines and/or lipopolysaccharide. The aim of this study was to investigate the production of NO via iNOS in specific liver cell populations during toxin-mediated and obstructive hepatic injury and fibrogenesis. After a single dose of carbon tetrachloride, iNOS mRNA and nitrite (a metabolic product of NO) were detected only in Kupffer cells. They were not detectable in any cell type after recurrent administration of carbon tetrachloride, including in animals with far advanced cirrhosis (i.e., portal hypertension and/or ascites). After bile duct ligation, a mechanistically different form of liver injury and fibrogenesis, iNOS mRNA and nitrite were identified in all nonparenchymal cells but not in hepatocytes. Twenty-four hours after bile duct ligation, iNOS mRNA and NO production were greatest in Kupffer cells, but after prolonged bile duct ligation, iNOS was found predominantly in sinusoidal endothelial cells. These data indicate that iNOS expression varies temporally and spatially in the liver after injury and also varies with the type of insult.

scholarly journals Review of experimental models for inducing hepatic cirrhosis by bile duct ligation and carbon tetrachloride injection

2012 ◽  
Vol 27 (8) ◽  
pp. 589-594 ◽  
Author(s):  
Thamirys Guimarães Marques ◽  
Eleazar Chaib ◽  
Juliana Hamati da Fonseca ◽  
Ana Cecília Rodrigues Lourenço ◽  
Felipe Duarte Silva ◽  
...  
Keyword(s):  
Liver Cirrhosis ◽  
Carbon Tetrachloride ◽  
Bile Duct ◽  
Web Sites ◽  
Bile Duct Ligation ◽  
Experimental Models ◽  
Duct Ligation ◽  
Experimental Liver Cirrhosis ◽  
Experimental Liver ◽  
Better Than

PURPOSE: To present a review about a comparative study of bile duct ligation versus carbon tetrachloride Injection for inducing experimental liver cirrhosis. METHODS: This research was made through Medline/PubMed and SciELO web sites looking for papers on the content "induction of liver cirrhosis in rats". We have found 107 articles but only 30 were selected from 2004 to 2011. RESULTS: The most common methods used for inducing liver cirrhosis in the rat were administration of carbon tetrachloride (CCl4) and bile duct ligation (BDL). CCl4 has induced cirrhosis from 36 hours to 18 weeks after injection and BDL from seven days to four weeks after surgery. CONCLUSION: For a safer inducing cirrhosis method BDL is better than CCl4 because of the absence of toxicity for researches and shorter time for achieving it.

Vitamin D inhibits development of liver fibrosis in an animal model but cannot ameliorate established cirrhosis

2015 ◽  
Vol 308 (2) ◽  
pp. G112-G120 ◽  
Author(s):  
Shirley Abramovitch ◽  
Efrat Sharvit ◽  
Yosef Weisman ◽  
Amir Bentov ◽  
Eli Brazowski ◽  
...  
Keyword(s):  
Vitamin D ◽  
Growth Factor ◽  
Bile Duct ◽  
Liver Fibrosis ◽  
Bile Duct Ligation ◽  
Active Form ◽  
Preventive Treatment ◽  
Antifibrotic Effect ◽  
Duct Ligation

1,25(OH)2D3, the active form of vitamin D, has an antiproliferative and antifibrotic effect on hepatic stellate cells. Our aim was to investigate the potential of 1,25(OH)2D3 to inhibit the development of liver fibrosis and to ameliorate established fibrosis in vivo. The antifibrotic effect of 1,25(OH)2D3 was investigated in a thioacetamide (TAA) model (as a preventive treatment and as a remedial treatment) and in a bile duct ligation model. In the preventive model, rats received simultaneously intraperitoneum injection of TAA and/or 1,25(OH)2D3 for 10 wk. In the remedial model, rats were treated with TAA for 10 wk and then received 1,25(OH)2D3 or saline for 8 wk. Fibrotic score was determined by Masson staining. Collagen I, α-smooth muscle actin (α-SMA), tissue inhibitor of metalloproteinase-1 (TIMP1), platelet-derived growth factor (PDGF), and transforming growth factor-β (TGF-β) expression were measured by Western blot analysis and real-time PCR. Hypercalemia was detected by chemistry measurements. Preventive treatment of 1,25(OH)2D3 significantly suppressed liver fibrosis both macroscopically and microscopically and significantly lowered the fibrotic score of the TAA + 1,25(OH)2D3 group compared with the TAA group. 1,25(OH)2D3 significantly inhibited expression of PDGF and TGF-β by ∼50% and suppressed the expression of collagen Iα1, TIMP1, and α-SMA by approximately three-, two-, and threefold, respectively. In contrast, 1,25(OH)2D3 was inefficient in amelioration of established liver fibrosis. Administration of 1,25(OH)2D3 to bile duct ligation rats led to a high mortality rate probably caused by hypercalcemia. We conclude that 1,25(OH)2D3 may be considered as a potential preventive treatment in an in vivo model but failed to ameliorate established cirrhosis.

scholarly journals CIRRHOSIS INDUCES APOPTOSIS IN RENAL TISSUE THROUGH INTRACELLULAR OXIDATIVE STRESS

2015 ◽  
Vol 52 (1) ◽  
pp. 65-71 ◽  
Author(s):  
Keli Cristina Simões da SILVEIRA ◽  
Cassiana Macagnan VIAU ◽  
Josiane Raskopf COLARES ◽  
Jenifer SAFFI ◽  
Norma Possa MARRONI ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Antioxidant Enzymes ◽  
Membrane Potential ◽  
Bile Duct ◽  
Mitochondrial Membrane Potential ◽  
Mitochondrial Membrane ◽  
Bile Duct Ligation ◽  
Decompensated Cirrhosis ◽  
Biliary Cirrhosis ◽  
Duct Ligation

Background Renal failure is a frequent and serious complication in patients with decompensated cirrhosis. Objectives We aimed to evaluate the renal oxidative stress, cell damage and impaired cell function in animal model of cirrhosis. Methods Secondary biliary cirrhosis was induced in rats by ligation of the common bile duct. We measured TBARS, ROS and mitochondrial membrane potential in kidney as markers of oxidative stress, and activities of the antioxidant enzymes. Relative cell viability was determined by trypan blue dye-exclusion assay. Annexin V-PE was used with a vital dye, 7-AAD, to distinguish apoptotic from necrotic cells and comet assay was used for determined DNA integrity in single cells. Results In bile duct ligation animals there was significant increase in the kidney lipoperoxidation and an increase of the level of intracellular ROS. There was too an increase in the activity of all antioxidant enzymes evaluated in the kidney. The percentage viability was above 90% in the control group and in bile duct ligation was 64.66% and the dominant cell death type was apoptosis. DNA damage was observed in the bile duct ligation. There was a decreased in the mitochondrial membrane potential from 71.40% ± 6.35% to 34.48% ± 11.40% in bile duct ligation. Conclusions These results indicate that intracellular increase of ROS cause damage in the DNA and apoptosis getting worse the renal function in cirrhosis.

Peripheral vascular neuroeffector mechanisms in experimental cholestasis

1993 ◽  
Vol 265 (3) ◽  
pp. G579-G586 ◽  
Author(s):  
G. Jacob ◽  
O. Said ◽  
J. Finberg ◽  
A. Bomzon
Keyword(s):  
Electrical Stimulation ◽  
Bile Duct ◽  
Vascular Reactivity ◽  
Bile Duct Ligation ◽  
Norepinephrine Uptake ◽  
Pithed Rats ◽  
Duct Ligation ◽  
Adrenoceptor Agonists

Jaundiced patients have systemic hypotension and are more susceptible to hemorrhagic shock than nonjaundiced individuals. We have hypothesized that the mechanism whereby these cardiovascular complications arise is linked to a disturbance of the vascular neuroeffector process in the cardiovascular system. With the use of 3-day bile duct-manipulated (sham-operated) and bile duct-ligated rats, we have evaluated alpha-adrenoceptor function and amine uptake using in vivo and in vitro techniques. Blunted pressor responsiveness to norepinephrine, electrical stimulation, and the alpha 1-adrenoceptor agonists, methoxamine and phenylephrine, was observed in the bile duct-ligated pithed rats. In contrast, normal responsiveness to BHT-933 and clonidine, the alpha 2-adrenoceptor agonists, was seen in these animals. The uptake 1 blocker, cocaine, caused potentiation of equal magnitudes of the pressor responsiveness to electrical stimulation and norepinephrine in the sham-operated and bile duct-ligated pithed rats. In aortic rings prepared from the bile duct-ligated rats, blunted in vitro vascular reactivity to norepinephrine and the same alpha 1-adrenoceptor agonists was seen. Bile duct ligation had no effect on norepinephrine uptake or its kinetics in stressed and unstressed arterial rings and portal veins. We have thus concluded that bile duct ligation induces a defect in the functional expression of cardiovascular alpha 1-adrenoceptors without any effects on the activity of alpha 2-adrenoceptors or norepinephrine uptake.

scholarly journals Regulation of cholesterol and bile acid homoeostasis in bile-obstructed rats

1991 ◽  
Vol 280 (2) ◽  
pp. 373-377 ◽  
Author(s):  
S Dueland ◽  
J Reichen ◽  
G T Everson ◽  
R A Davis
Keyword(s):  
Bile Acid ◽  
Bile Duct ◽  
Liver Function ◽  
Urinary Excretion ◽  
Bile Acids ◽  
Bile Duct Ligation ◽  
Microsomal Cytochrome ◽  
Duct Ligation ◽  
Cytochrome P 450

We examined how total blockage of biliary excretion, the major pathway through which cholesterol and bile acids are removed from the body, affects liver function, cholesterol and bile acid metabolism and homoeostasis. After 4 weeks of bile-duct ligation, rats showed impaired liver function, as documented by elevations in serum bilirubin and alkaline phosphatase activity. Moreover, bile-duct ligation decreased by about 30% both the amount of microsomal cytochrome P-450 in the liver and the elimination of aminopyrine in vivo, a reliable index in vivo of microsomal mixed-function oxidase activity. Cholesterol and bile acid contents in livers of bile-duct-ligated rats were doubled compared with sham-operated controls. Despite the increase in the contents of cholesterol and bile acids in liver, activities of the respective rate-limiting enzymes, 3-hydroxy-3-methylglutaryl-CoA reductase and cholesterol 7 alpha-hydroxylase, were doubled. Serum concentrations of bile acids and free cholesterol increased 25- and 4-fold respectively. The large increase in serum bile acids was associated with a 380-fold increase in the urinary excretion of bile acids. Although there is a general decrease in cytochrome P-450 content and drug metabolism involving cytochrome P-450-containing hydroxylases, the activity of cholesterol 7 alpha-hydroxylase, also a cytochrome P-450-containing enzyme, is actually increased. These data show that complete obstruction of the bile duct results in the selective impairment of microsomal cytochrome P-450. Increased activity of 7 alpha-hydroxylase, bile acid synthesis and urinary excretion provides an alternative excretory pathway that helps to maintain cholesterol homoeostasis when the biliary excretory pathway is eliminated.

scholarly journals Comparing distress of mouse models for liver damage

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Guanglin Tang ◽  
Nico Seume ◽  
Christine Häger ◽  
Simone Kumstel ◽  
Kerstin Abshagen ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Carbon Tetrachloride ◽  
Bile Duct ◽  
Animal Models ◽  
Mouse Models ◽  
Liver Damage ◽  
Bile Duct Ligation ◽  
Characteristic Curve ◽  
Support Vector ◽  
Duct Ligation

AbstractIn order to foster animal welfare as well as high quality of research, many countries regulate by law that the severity of animal experiments must be evaluated and considered when performing biomedical research. It is well accepted that multiple parameters rather than a single readout parameter should be applied to describe animal distress or suffering. However, since the performance of readout parameters for animal distress is rarely defined and methods for multivariate analysis have only in rare cases been used, it is not known which methodology is most appropriate to define animal distress. This study used receiver operating characteristic curve analysis to quantify the performance of burrowing activity, body weight change and a distress score of mice after induction of liver damage by bile duct ligation or carbon tetrachloride. In addition, Support Vector Machine classification was used to compare the distress of these mouse models. This approach demonstrated that bile duct ligation causes much more distress than carbon tetrachloride-induced liver damage. This study, therefore, provides a prototype how to compare two animal models by considering several readout parameters. In the future these or similar methods for multivariate analysis will be necessary, when assessing and comparing the severity of animal models.

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