Thioacetamide- and Carbon Tetrachloride-Induced Liver Cirrhosis

Dashti, H.; Jeppsson, Bengt; Hägerstrand, Inga; Hultberg, Björn; Uppugunduri, Srinivas; Abdulla, M.; Bengmark, S

doi:10.1159/000129007

Cited by 122 publications

(107 citation statements)

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“…18,28 TAA displays a longer latency between the exposure to the drug and the development of liver injury. 3,29 TAA also leads to more periportal infiltrates and more pronounced ductal proliferation, appearance of acidophilic bodies, and vacuolated nuclei with prominent nucleoli, as well as more pronounced hepatocyte vacuolization. 18,19 Bile duct ligation and repeated application of CCl 4 have traditionally been employed as the most widely used experimental model of fibrosis.…”

Section: Mechanisms and Pattern Of Liver Injurymentioning

confidence: 98%

Standard Operating Procedures in Experimental Liver Research: Thioacetamide model in mice and rats

et al. 2015

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In addition to carbon tetrachloride (CCl 4 ), thioacetamide (TAA) represents a second widely used model for the induction of experimental liver fibrosis, but can also be employed for the development of acute liver failure and liver tumours. While TAA itself is not hepatotoxic, its reactive metabolites covalently bind to proteins and lipids thereby causing oxidative stress and centrilobular necrosis. Compared with CCl 4 , TAA leads to more periportal infiltrates and more pronounced ductal proliferation. While TAA has been shown to induce liver fibrosis development in several different mouse strains, wide variations in the administration routes, doses and treatment durations have been reported. Therefore, an adoption of a universal standard operating procedure for the administration of TAA is urgently needed. For that purpose, we are presenting here two TAA models (intraperitoneal administration of 150 mg/kg of TAA three times per week for 11 weeks in rats, and TAA administration in drinking water at 300 mg/L for 2-4 months in mice) with which we have had success in reliably and reproducibly developing chronic liver injury and fibrosis.

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Section: Mechanisms and Pattern Of Liver Injurymentioning

confidence: 98%

Standard Operating Procedures in Experimental Liver Research: Thioacetamide model in mice and rats

et al. 2015

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“…On the other hand, chronic TAA treatment at a low dose to rats induces cirrhosis and hepatic tumors (Müller et al, 1988;Fontana et al, 1996;Kawai et al, 2009). The characteristic features of TAA-induced hepatotoxicity in rats resemble those of human cirrhosis (Müller et al, 1988;Dashti et al, 1989;Sato et al, 2000), and rats chronically treated with TAA exhibit memory impairment (Méndez et al, 2008a). Therefore, we hypothesized that chronic TAA treatment of rats might induce HE-like neuropsychiatric symptoms, such as memory impairment and mental disturbance.…”

Section: Introductionmentioning

confidence: 99%

Behavioral and biochemical characterization of rats treated chronically with thioacetamide: proposal of an animal model for hepatic encephalopathy associated with cirrhosis

et al. 2012

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-Hepatic encephalopathy (HE) is a syndrome observed in patients with liver dysfunction such as hepatitis and cirrhosis, and is characterized by cognitive impairment, personality changes, and a depressed level of consciousness. The detailed mechanism underlying the pathogenesis of HE remains unclear. In the present study, our aim was to establish an animal model for HE with cirrhosis. Therefore, we carried out behavioral and biochemical analysis of cirrhotic rats after treatment with thioacetamide (TAA) for 20 weeks. The rats subjected to chronic TAA treatment (TAA rats) showed reduction of cognitive scores in the novel object recognition test (NOR), and a decrease in immobility and an increase in swimming in the forced swim test (FST). In biochemical analyses, the TAA rats exhibited elevated blood levels of ammonia, and increased metabolic activities of serotonergic and noradrenergic neurons in the brain, while the levels of Glu and GABA were not affected. Post-oral treatment of lactulose, a clinically utilized drug for HE, effectively reduced the elevated blood ammonia levels, and restored the reduced cognitive scores and the decreased immobility, without any effects on neurotransmitter contents in the brain, compared with the control. These results indicated lactulose-restorable memory disturbance and irritated mood in the TAA rats. In other words, rats treated chronically with TAA are a potential model for cirrhosis-HE, and the combination of NOR and FST in TAA rats may be useful as a simple assay system for the screening and development of anti-HE agents.

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“…In contrast, very low activities were measured in liver homogenates and serum from cows. Influence of thioacetamide, a hepatotoxin, on the activity of the serum TRH-DE When rats were treated with thioacetamide, an agent which is known to induce liver cirrhosis [33,34], we observed a rapid decrease in the activity of the serum TRH-DE within 18 days (Fig. 1).…”

Section: R E S U L T S Degradation Of Trh By Serum and Tissue Homogenmentioning

confidence: 88%

Purification and characterization of the thyrotropin‐releasing hormone (TRH)‐degrading serum enzyme and its identification as a product of liver origin

Schmitmeier¹,

Thole²,

Bader

et al. 2002

European Journal of Biochemistry

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Previous biochemical studies have indicated that the membrane-bound thyrotropin-releasing hormone (TRH)-degrading enzyme (TRH-DE) from brain and liver and the serum TRH-DE are derived from the same gene. These studies also suggested that the serum enzyme is of liver origin. The present study was undertaken to verify these hypotheses. In different species, a close relationship between the activities of the serum enzyme and the particulate liver enzyme was noticed. The activity of the serum enzyme decreased when rats were treated with thioacetamide, a known hepatotoxin. With hepatocytes cultured in a sandwich configuration, release of the TRH-DE into the culture medium could also be demonstrated. The trypsin-solubilized particulate liver TRH-DE and the serum TRH-DE were purified to electrophoretic homogeneity. Both enzymes and the brain TRH-DE were recognized by a monoclonal antibody generated with the purified brain enzyme as antigen. Lectin blot analysis indicated that the serum enzyme and the liver enzyme are glycoproteins containing a sugar structure of the complex type, whereas the brain enzyme exhibits an oligomannose/hybrid glycostructure. A molecular mass of 97 000 Da could be estimated for all three enzymes after deglycosylation and SDS/PAGE followed by Western blotting. Fragment analysis of the serum TRH-DE revealed that the peptide sequences correspond to the cDNA deduced amino-acid sequences of the membrane-bound brain TRH-DE, whereby two peptides were identified that are encoded by exon 1. These data strongly support the hypothesis that the TRH-DEs are all derived from the same gene, whereby the serum enzyme is generated by proteolytic cleavage of the particulate liver enzyme.Keywords: TRH-degrading enzyme (TRH-DE); serum; liver; brain; characterization.The signal substance thyrotropin-releasing hormone (TRH), a hypothalamic hypophysiotropic neuropeptide hormone (reviewed in [1,2]) and a peptidergic neurotransmitter/neuromodulator (reviewed in [3,4]), is known to be rapidly inactivated by the brain TRH-degrading enzyme (TRH-DE), an ectoenzyme located on the surface of neuronal cells, as well as by the soluble serum TRH-DE. The highest activity of the membrane-bound TRH-DE is found in brain and significant activities are also detected in retina, lung and liver but not in other tissues such as heart, kidney and muscle [5][6][7]. Because the membrane-bound brain TRH-DE and the serum TRH-DE exhibit the same extraordinary high degree of substrate specificity and identical enzyme-chemical characteristics [8][9][10][11][12][13][14] it has been suggested that both enzymes are derived from the same gene.Based on the observation that the developmental pattern of the particulate liver TRH-DE and the serum TRH-DE are almost identical it has been proposed that the serum TRH-DE, like most serum enzymes and proteins, might be of liver origin [9,15]. This interpretation was supported by the findings that the activities of the particulate liver enzyme, like the serum enzyme [16][17][18], is also regulated by thyroid h...

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Thioacetamide- and Carbon Tetrachloride-Induced Liver Cirrhosis

Cited by 122 publications

References 10 publications

Standard Operating Procedures in Experimental Liver Research: Thioacetamide model in mice and rats

Standard Operating Procedures in Experimental Liver Research: Thioacetamide model in mice and rats

Behavioral and biochemical characterization of rats treated chronically with thioacetamide: proposal of an animal model for hepatic encephalopathy associated with cirrhosis

Purification and characterization of the thyrotropin‐releasing hormone (TRH)‐degrading serum enzyme and its identification as a product of liver origin

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