Effect of fibrin glue occlusion of the hepatobiliary tract on thioacetamide-induced liver failure.

BACKGROUND: Expression and activation of hepatocyte growth factor (HGF) is stimulated by a complex system of interacting proteins, with thrombin playing an initial role in this process. The impact of temporary occlusion of the hepatobiliary tract with fibrin glue (major component thrombin) on the HGF system in acute and chronic liver damage in a rat model was investigated. METHODS: Chronic liver damage was induced in 40 rats by daily intraperitoneal application of thioacetamide (100 mg/kg) for 14 days. After 7 days half of them received an injection of 0.2 mL fibrin glue into the hepatobiliary system. Daily intraperitoneal administration of thioacetamide continued for 7 consecutive days. The rats were then sacrificed for blood and tissue analysis. Acute liver failure was induced in 12 rats by intraperitoneal administration of a lethal dose of thioacetamide (500 mg/kg per day for 3 days) after an injection with 0.2 mL fibrin glue into their hepatobiliary tract. Survival rates and histological outcome were investigated and compared with control animals. RESULTS: Fibrin glue occluded rats showed significantly lower liver enzyme activities and serum levels of bilirubin, creatinine and urea nitrogen. Immunohistochemistry revealed a significant increase in c-met-, HGFalpha- and especially HGFbeta-positive cells. Rats subjected to a lethal dose of thioacetamide survived when fibrin glue was applied 24 hours prior to the toxic challenge. These animals showed normal liver structure and no clinical abnormalities. CONCLUSION: Fibrin glue occlusion of the hepatobiliary tract induces therapeutic and prophylactic effects on chronic and acute liver failure by stimulating the HGF system. Therefore, fibrin glue occlusion might be useful in treating toxic liver failure.

Effect of 4-phenyl-1,3-dithia-2-thioxo-cyclopent-4-ene on liver injury induced by repeated exposure to galactosamine plus carbon tetrachloride in rats.

The protective effects of 1,3-dithia-2-thioxo-cyclopent-4-ene (DT827A),4-phenyl-1,3-dithia-2-thioxo-cyclopent- 4-ene (DT827B) and 4-(4-fluorophenyl)-1,3-dithia-2-thioxo-cyclopent-4-ene (DT827C) on liver injury induced by D-galactosamine plus carbon tetrachloride (D-GalN + CCl4) and that of DT827B on liver injury induced by thioacetamide were studied using male rats. Out of the three DT827 series of compounds, DT827B was more effective on liver injury induced by the combination exposure to D-GalN + CCl4 for 4 weeks, and accordingly the following two experiments were carried out using DT827B only. Twelve-week administration of DT827B at dose levels of 5, 10 and 20 mg/kg/day revealed a therapeutic effect against liver injury induced by D-GalN + CCl4 dose-dependently, and another twelve-week administration of DT827B at the same three dose levels also revealed a therapeutic effect against liver injury induced by thioacetamide dose-dependently. A hepatoprotective potential of DT827B was suggested under the conditions of these studies.

Inhibition of ornithine aminotransferase by 5-fluoromethylornithine: protection against acute thioacetamide intoxication by elevated tissue ornithine levels.

5-Fluoromethylornithine (5FMOrn) is a selective inactivator of ornithine aminotransferase. Its administration causes a dramatic increase of ornithine concentrations in all tissues. Treatment of mice with 20 mg.kg-1 5FMOrn shortly before or after a lethal dose (600 mg.kg-1, intraperitoneally) of thioacetamide (TAA), followed by a second dose 24 hr later, prevented death of 60% of the mice. Pathologic symptoms of TAA intoxication (liver haemorrhage, elevation of amino acids in blood and tissues, diminution of liver spermidine and spermine concentrations, elevation of the activity of liver enzymes in the plasma) were significantly ameliorated by the treatment. The liver protective action of 5FMOrn is related to the elevation of ornithine concentration, as appears from the fact that other, less selective inactivators of ornithine aminotransferase, also produced some protection against acute intoxication with TAA, but not a structurally related compound with no effect on this enzyme.

[Effect of prior starvation on the development of acute thioacetamide-induced liver damage in rats]. / Vliianie predvaritel'nogo golodaniia na razvitie ostrogo pechenochnogo povrezhdeniia tioatsetamidom u krys.

The effect of previous fasting on the liver morphological changes and microsomal cytochrome P-450 and b5 content was studied in thioacetamide-induced (100 mg/kg) rat liver necrosis. Starvation for 48 hours immediately before thioacetamide administration aggravates the dystrophic and necrotic processes, as revealed by histology, electron microscopic investigations and serum aminotransferase activity. The liver microsomal cytochrome P-450 concentration tended to decrease after thioacetamide challenge, with fasting resulting in a more significant loss of cytochrome P-450. Cytochrome b5 content, however, was found to increase in acute liver necrosis induced by thioacetamide.

The effect of some hepatotoxins on the sulphoxidation of cimetidine in rat.

Sulphoxidation of cimetidine was investigated in male and female rats after pretreatment with the hepatotoxins allyl alcohol, dl-ethionine, thioacetamide and carbon tetrachloride. There was a marked sex difference in cimetidine sulphoxidation in response to the hepatotoxin pretreatment. All the hepatotoxins enhanced cimetidine sulphoxidation in the male rat (P less than 0.01). Carbon tetrachloride and thioacetamide inhibited cimetidine sulphoxidation in the female rat (P less than 0.01) but dl-ethionine and allyl alcohol had no effect on this metabolic pathway.

Efecto de la tioacetamida sobre el hígado de rata en condiciones de diferente aporte de proteína en la diet a / Effect of thioacetamide on rat liver under different protein intakes conditions in the diet

En países subdesarrollados la mayoría de la población está expuesta a la deficiencia proteínica en la alimentación y consecuentemente al síndrome de prekwashiorkor, acompañado de bajas defensas del organismo. En estas condiciones aumenta la sensibilidad del humano a los agentes ambientales, cuyo número crece día a día y plantea un serio problema de salud, fundamentando la búsqueda de la fórmula alimentaria ópitma como medida protectora. El propósito de este trabajo es corroborar si la proteína de la alimentación puede fungir como antídoto de la acción tóxica de la tioacetamida que recae sobre el hígado y, al igual que la inanición proteínica, afecta la estructura y las funciones de los hepatocitos. El estudio se realizó a nivel subcelular (lisosomas) en aspectos enzimático (enzimas marcadoras-fosfatasa ácida, ribonucleasa ácida y catepsina) y morfológico. Se encontró: la tiocetamida en condiciones de aporte normal proteínico (18,5%) en la dieta provoca cambios moderados característicos (necrosis centrolobular, alteración del patrón enzimático y de la permeabilidad de membranas lisosomales). En deficiencia proteínica (4%) la afección es mucho más severa histológica y enzimáticamente (necrosis extensa, infiltración periportal grasa, alteración del patrón enzimático, permeabilidad de membranas lisosomal y celular). En condiciones de alimentación rica en proteína (44.5%) los cambios histológicos son discretos, sin afección enzimática ni estructural. Se concluye: el aporte elevado de proteína en la dieta surte en ratas efecto de antídoto de la acción hepatotóxica de la tioacetamida, hecho que plantea la posible utilidad de la proteína dietética en la protección del organismo contra la contaminación ambiental

Changes in intra- and extrahepatic VLDL in the rat following acute injury by thioacetamide. A morphometric and biochemical study.

The effect of a single dose of TAA (100 mg/kg body weight) on intra- and extrahepatic lipoproteins of the very low density (VLDL) type was studied in rats by morphometric and biochemical methods. For a better quantification of VLDL in the periportal (zone 1) and centrilobular (zone 3) hepatocytes of control and TAA-intoxicated livers, colchicine was used as an inhibitor of hepatic lipoprotein secretion. Generally, there exists a great functional heterogeneity between the hepatocytes of zone 1 and 3 in the colchicine-treated controls manifested in a significantly different accumulation rate of VLDL particles. The mean number of VLDL particles per vesicle, the mean secretory vesicle size and the volume density of the electron-lucent secretory vesicles are two times larger in hepatocytes of zone 1 than zone 3. The volume of the VLDL particles amounts to 7.3 X 10(-5) microns3 and 22 X 10(-5) microns3 in the peri- and centrilobular regions. On the other hand, there is no significant lobular-zonal difference in the number of light and dark secretory vesicles. Within 48 h TAA treatment causes a reduction in the number of VLDL particles/100 microns 2 in zone 1 and 3 by 66% and 61%, whereas the number of light secretory vesicles is decreased by 31% and 58%, respectively. The volume density of the latter is significantly diminished only in zone 1. Moreover, the VLDL particle volume is reduced to nearly 50% in each lobular zone examined. The data obtained after TAA treatment from the electron-dense secretory vesicles do not differ significantly from those of the colchicine-treated controls. Acute TAA intoxication lowers the hepatic VLDL-TG output by about 50% in comparison with controls. The steady state of the serum TG concentration after TAA application implies that the clearance of TG from the serum must be diminished to the same extent as the hepatic TG output is found to decrease due to acute liver injury. The results presented here support our view that acute TAA intoxication lowers the hepatic VLDL output by inhibiting the intracellular formation of VLDL. The intrahepatic degradation of the newly synthesized VLDL seems to be unaffected. Despite the fact that the substructure of the hepatocytes in zone 3 is much more changed than in zone 1 after TAA treatment the quantitative data on the VLDL secretory products provide evidence that the process of lipoprotein formation is disturbed to nearly the same extent by TAA both in zone 1 and 3.

Long-term fate of the bile duct cells proliferated during chronic thioacetamide poisoning.

The cell composition of the biliary proliferations induced by thioacetamide administration was investigated. At the end of the intoxication period the main cell types identified among the neoformed bile duct cells were as follows: i) poorly differentiated cells (oval cells) usually arranged in clusters or tiny cords, provided with a great amount of free ribosomes; ii) cells arranged in bile ducts of normal appearance; iii) cells arranged in bile ducts and showing intestinal metaplasia. After withdrawal of TAA most of the biliary proliferations disappeared; in the remaining ones, where the incorporation of 3H-thymidine was still appreciable, significant changes in the bile duct cell composition were evident; in fact whereas the oval cells were no longer identifiable, those suggesting an intestinal metaplasia underwent a relative increment as well as those displaying butyrocholinesterase activity; cells devoid of junctional apparatus and filled with free ribosomes were also seen. Some of the reported finding could support the hypothesis that the biological meaning of the different cell types arisen during intoxication is different; some of them could be due to a reactive hyperplasia, while other could be considered as representing a preneoplastic step.

Copper and zinc content of liver, heart, skeletal muscle, and brain, in acute thioacetamide intoxication of rats.

It has been demonstrated that acute thioacetamide intoxication causes a significant increase in copper and zinc in the dystrophic liver of rats. Heart, skeletal muscle, cerebrum and cerebellum showed neither significant deviations of copper and zinc content, nor noticeable histopathologic changes in comparison with controls. Thus, hepatotropia in thioacetamide intoxication receives minimal pathological confirmation.

Long-term evolution of the main changes induced by thioacetamide on hepatocytes.

The results of an electron microscopic study of the changes in hepatocytes induced by chronic intoxication with thioacetamide are reported. During the poisoning aspecific toxic changes are intermingled with progressive, preneoplastic ones. The main cell subpopulations identified are: 1) large hepatocytes with smooth endoplasmic reticulum (SER) hypertrophy, with or without rough endoplasmic reticulum (RER) neoformation and glycogen storage, which is starvation resistant; 2) smaller hepatocytes, where RER hypertrophy and ribosome accumulation are the prominent features. Such a pattern persists for months. After the withdrawal of the drug most of the cell changes disappear. However, during this time a simplification of the liver structure and cell composition takes place, allowing a sequence of cell events which seem relevant for establishment of neoplastic progression. The SER-hypertrophied cell appears first and gives rise, via several intermediate stages, to the RER-hypertrophied one, which is believed to play a key role as the ultimate precursor of cancer cells.

[The effect of sulfur compounds (N-acetylhomocysteine-thiolactone and penicillamine) on liver collagen metabolism in chronic thioacetamide poisoning]. / Der Einfluss von Thio-Verbindungen (N-Acetylhomocysteinthiolakton und Penicillamin) auf den Kollagenstoffwechsel der Leber bei chronischer Thioacetamid-Intoxikation.

The influence of N-acetyl-homocysteine-thiolactone (AHCT) and penicillamine on experimental thioacetamide (TAA)-induced liver fibrosis was investigated. TAA causes an increase in liver collagen content, which can partly be prevented by penicillamine and AHCT. This prevention is most effective, when the TAA-intoxication started earlier than the therapy with these two substances. The therapeutic effect of penicillamine is achieved by an inhibition of collagen biosynthesis and cross-linking (with an increase in the easily soluble collagen fractions). In the case of AHCT the inhibition of pathological collagen synthesis in experimental liver fibrosis cannot be explained by disturbed collagen cross-linking or increased collagen solubility. Whether collagen synthesis is inhibited and/or other influences of AHCT are present has still to be analyzed.

Actinide transport across cell membranes.

Protactinium uptake into the normal liver does not exceed 3%, but when the phospholipid levels in the liver are elevated by administration of thioacetamide this uptake increases to 31%. Phosphatidic acid, which is absent from the normal liver, has been shown to extract protactinium into organic solvents. However, phosphatidylserine, a component of normal liver cell membranes, does not extract protactinium. It might be conjectured that this is why so little protactinium is taken up by the normal liver. The hypothesis is advanced that phosphatidylserine, which is known to complex plutonium, americium and curium, may regulate the uptake of these elements by liver.