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Biomedical subjects

B Tuchweber

Publications and source records attributed to B Tuchweber.

At least 91 records · Page 5Linked to original sources
PubMed1985

Hepatotoxicity of sodium valproate in ornithine transcarbamylase-deficient mice.

Susceptibility to sodium valproate (SV) hepatotoxicity was investigated in male sparse-fur mutant (spf/Y) mice with X-linked ornithine transcarbamylase (OTC) deficiency, as compared to normals (+/Y). SV was given in drinking water, in increasing concentrations of 0, 0.05, 0.15 and 0.25%. Actual SV intake was similar in both groups. There were no significant changes in orotate excretion, but alpha-amino nitrogen increased progressively with SV intake in both groups. Valproate-treated animals also had a significant increase in hepatic carbamyl phosphate synthetase-I (CPS-I) activity. OTC-deficient spf/Y mice showed 33% mortality and morbidity at 0.05-0.15% valproate, while normal mice remained non-symptomatic. spf/Y Mice also showed a higher incidence of hepatocellular necrosis, microvesicular steatosis and polymorphic infiltration. Centrilobular necrosis was seen only in symptomatic OTC-deficient mice, indicating an idiosyncratic hepatotoxic response which may be different from the dose-related effects seen in all SV-treated mice. Electron microscopy of liver sections from severely affected spf/Y mice showed marked abnormalities of mitochondria, which appeared swollen or rounded. The rough endoplasmic reticulum was dilated and filled with a flocculent material. It is postulated that the idiosyncratic response in OTC-deficient mice may be caused by an interaction between a metabolic aberration of mitochondria and toxic metabolites of valproate.

Animals↗
PubMed1984

Effect of lithocholic acid on cholesterol synthesis and transport in the rat liver.

The cellular origin of cholesterol which accumulates in liver cell plasma membrane fractions enriched in bile canalicular structures after lithocholic acid treatment was determined in vivo. Rats were given [3H]cholesterol followed 16 h later by [2-14C]mevalonic acid, [2-14C]acetic acid or lithocholic acid. Lithocholic acid injection enhanced the de novo synthesis of cholesterol in the microsomes and both compounds were transported to the bile canalicular membranes. However, in vitro studies demonstrated that lithocholic acid is capable of stripping cholesterol from microsomal membranes even in the absence of increased de novo synthesis. This suggests that transfer of cholesterol from subcellular organelles (microsomes) to bile canalicular membranes may be the initial step in the development of lithocholic acid-induced cholestasis.

Acetates↗
PubMed1984

Lithocholic acid-cholesterol interactions in rat liver plasma membrane fractions.

This study was designed to elucidate the steps involved in the incorporation of lithocholic acid and the increase in cholesterol in liver plasma membranes after lithocholic acid injection. In vitro, cholesterol incorporation or binding to liver plasma membrane fractions enriched in bile canalicular structures occurred only when cholesterol was added simultaneously with lithocholic acid. The addition of cholic acid did not prevent the incorporation or binding of lithocholic acid and of cholesterol. However, when cholic acid was incubated with membranes already containing lithocholic acid and cholesterol, the ratio of cholesterol to lithocholic acid increased from 2 to more than 3 via a reduction of lithocholic acid. The binding of lithocholic acid and cholesterol to membranes rose 5-fold in the presence of cytosolic proteins. By electron microscopy the canalicular membrane structures with a high cholesterol content exhibited few microvilli, and their lumen appeared to have collapsed. These data suggest that simultaneous interaction of lithocholic acid and cholesterol, and not prior incorporation or binding of lithocholic acid to the membrane, may be a prerequisite to cholesterol accumulation in the membrane.

Animals↗
PubMed1984

Protection by silibinin against Amanita phalloides intoxication in beagles.

A single oral dose of the lyophilized deathcap fungus Amanita phalloides (85 mg/kg body wt) caused gastrointestinal signs of diarrhea, retching, and vomiting in beagles after a latent period of 16 hr. The pathologic lesions; the increases in serum transaminase (GOT, GPT), alkaline phosphatase, and bilirubin, as well as the fall in prothrombin time all indicated that liver damage was maximal at about 48 hr after poisoning. Four of twelve dogs given A. phalloides died with signs of hepatic coma within 35 to 54 hr with the biochemical values in the survivors reverting to normal by the ninth day. Silibinin administration (50 mg/kg) 5 and 24 hr after intoxication suppressed the serum changes and the fall in prothrombin time. The degree of hemorrhagic necrosis in the liver was markedly reduced, and none of the silibinin-treated dogs died.

Alanine Transaminase↗
PubMed1984

Liver lysosomal enzymes in rats during long-term dietary restriction. 1. Changes during the developmental period of life.

The specific activities of the lysosomal enzymes acid phosphatase, beta-galactosidase, arylsulphatase B and cathepsin D were determined in homogenates of livers of rats fed ad libitum and of rats subjected to long-term dietary restriction (10%, 30% and 50% of diet consumed by the ad libitum group). Dietary restriction began soon after weaning and animals were sacrificed 3, 9, 15 and 24 weeks later. Dietary restriction influenced all four enzymes but the changes depended on the enzyme as well as on the degree and duration of the dietary restriction. Total activity of acid phosphatase increased significantly at 3 weeks of restriction but only in the 50% group. The activity returned to normal values at 9 weeks. Arylsulphatase B increased in all experimental groups with a more pronounced change observed at 3 weeks and in the more severely restricted rats. No notable change in the activities of beta-galactosidase and cathepsin D activities was observed. Changes in the liver ultrastructure paralleled the biochemical changes seen at 3 weeks. Numerous autophagic vacuoles and dense bodies resembling age pigments were formed in the hepatocytic cytoplasm. Mitochondrial enlargement, increased matrical density and rough endoplasmic reticulum fragmentation were also noted. Few of these changes were observed at 9 weeks, and the hepatocyte's morphology was virtually normal at 15 and 24 weeks. The marked changes seen at 3 weeks may be a manifestation of the body's adaptive processes to the nutritional stress.

Acid Phosphatase↗
PubMed1983

Prevention of lithocholate--induced cholestasis by cycloheximide, an inhibitor of protein synthesis.

Our previous investigations have shown that lithocholic acid (LCA)-induced cholestasis is associated with an increased synthesis of microsomal cholesterol which is transported with LCA and incorporated in the bile canalicular membrane. As the significance of these changes remains unknown the effect of interference with microsomal protein synthesis and/or with the cellular transport of cholesterol was studied. Male Wistar rats were injected i.p. with cycloheximide at the dose of 15 micrograms/100 g BW 3 times over a 24-hour period. After cannulating the common bile duct and collecting bile for one hour, the animals were either injected i.v. with 12 mumoles C14-LCA/100 g BW or with a 7.5% albumin solution and bile was collected for another hour. LCA injection in untreated animals reduced bile flow by more than 90% of control values. In contrast, bile flow in the group treated with cycloheximide and LCA was normal and did not differ from that of animals given cycloheximide alone. Bile salt secretion rate was increased in the cycloheximide-LCA group over the control groups. This was mainly due to the secretion of more than 80% of the injected LCA and was confirmed by the distribution of the radioactivity. By electron microscopy, the liver in the cycloheximide-LCA group did not show any of the well defined changes associated with LCA-induced cholestasis. These data suggest that microsomes play an important role in the pathogenesis of LCA cholestasis and that inhibition of microsomal protein synthesis can prevent its development.

Animals↗
PubMed1983

Taurine prevents cholestasis induced by lithocholic acid sulfate in guinea pigs.

The hypothesis that the amino acid used for the conjugation of sulfolithocholate (S-LCA) is a critical determinant of its cholestatic potential was tested in the guinea pig which conjugates 90% of its bile acids with glycine. Twelve groups of animals were used to study the effect of taurine feeding at a concentration of 0.5% in the drinking water for periods of 1, 3, and 5 days before an iv injection of 18 mumol/100 g body weight of S-LCA. Bile flow was monitored in 30-min aliquots over a 3-h period and the bile acid secretion as well as the glycine/taurine ratio of conjugated bile acids were determined. At the end of the various time periods, the livers were examined by light and electron microscopy. Within 3 days after taurine administration there was an increase in bile flow and a reversal of the glycine/taurine ratio with taurine conjugates becoming predominant. Liver morphology was unchanged except for a slight accumulation of lipids after 5 days of taurine feeding. In animals who were not pretreated with taurine, S-LCA injection led to a progressive decrease in bile flow such, that it was reduced to less than 20% at the end of the 3-h collection. S-LCA was conjugated almost exclusively with glycine. In contrast, in the groups fed taurine for 1, 3, and 5 days before the S-LCA injection, bile flow was comparable to that of the groups fed taurine alone. The S-LCA recovered in bile was to a large extent conjugated with taurine. S-LCA animals pretreated with taurine did not exhibit any liver cell changes while the group which had not received taurine before the S-LCA injection showed numerous cytoplasmic vacuoles with normal bile canaliculi. These data show that increasing the availability of taurine through dietary means may exert a protective effect against cholestasis induced by monohydroxy bile acids.

Animals↗
PubMed1982

Effect of silybin on phalloidin-actin interactions in vitro.

The possible antagonism between silybin and phalloidin an F-actin has been examined in vitro. Phalloidin protects F-actin against denaturation by potassium iodine, cytochalasin B, DNase and pronase. Silybin does not counteract the effect of phalloidin on F-actin. However, silybin alone slowed the rate of polymerization of actin, but this effect was moderate and obtained with very high concentrations. These results indicate that the site of action in vitro of silybin is not actin.

Actins↗
PubMed1982

Morphological aspects of manganese-bilirubin induced cholestasis.

Small doses of manganese or bilirubin administered alone to rats produce no morphologic alterations in the hepatocytes. However, combination of both treatments produced a rapid and severe decrease in bile flow that was paralleled by the appearance and aggravation of the cholestatic lesion: bile canaliculi progressively lost their microvilli; vacuolization occurred in the pericanalicular area and subsequently in the cytoplasm. When bile flow returned to normal, or when cholestasis was prevented by an injection of sulfobromophthalein or a pretreatment with phalloidin, no cholestatic signs were observed. A close correlation appears to exist between the presence of morphologic alterations and the decrease of bile flow in manganese-bilirubin cholestasis.

Animals↗
PubMed1982

Phalloidin-induced morphological and functional changes of rat liver.

The hepatotoxic effect of phalloidin, a mushroom poison, was examined in whole liver and in isolated liver cell plasma membranes. By electron microscopy, a thickening of the pericanalicular microfilamentous network was noted. Bile canalicular enriched plasma membrane fractions of livers from phalloidin-treated animals contained increased amounts of microfilaments. Analysis of the peptides in these fractions, by sodium dodecyl sulfate polyacrylamide gel electrophoresis, indicated that although the actin peptide bands were prominent, a band apparently corresponding to myosin was drastically reduced. The morphological change was accompanied by a reduced bile flow and biliary excretion of bile acids, proteins and the exogenous organic anion dibromosulphthalein. These changes may result from a modification of the microfilaments, suggesting a role of the microfilaments in the liver membrane structure and function.

Animals↗
PubMed1982

Bile acid composition in neonatal life in rats.

Bile acid (BA) metabolism was studied in the intestine, liver and plasma of rats at 0-1 day (neonates); 14 days (preweaning); 22 days (weaning) and 60 days (young adults) of age, as well as in the maternal tissues. In the intestine, total BA content (mumol/100 g body weight) decreased during neonatal life and reached maternal levels at 60 days. In the liver, BA increased up to 14 days and then decreased at 22 and 60 days of age, but these concentrations were higher than those found in the neonate and the mother. The serum concentrations in 14- and 22-day-old rats were more than 30 times higher than in the newborns. At 60 days, serum BA content was still twice that of the mother. BA composition in the intestine and the liver showed a reduction in 12 alpha-hydroxylated BA associated with an increase in chenodeoxycholic acid and 6 beta-hydroxylated BA during neonatal life. These data indicate an increased synthesis of chenodeoxycholic and 6 beta-hydroxylated BA after birth. It further suggests a possible defect in excretory mechanisms in neonatal life.

Aging↗
PubMed1982

[In vivo and in vitro effects of peptide extracts from Amanita virosa].

Cyclic peptides from the deadly mushroom Amanita virosa has been separated by methanolic extraction and chromatography on Sephadex. Three groups of peptides have been obtained: virotoxins, amaninamide and phalloidin. Virotoxins has been separated in two fractions named virotoxins A and virotoxins B. We have studied the properties of these two fractions of F actin in vitro and on mice in vivo. Our results show that virotoxins A and B protect F actin in vitro against chaotropic ions, depolymerization by DNAse I or cytochalasin B and heat denaturation. Virotoxins A and B increase the rate of polymerization of F actin. Virotoxins A and B are toxic compounds which produce hemorrhagic necrosis of liver that have been observed in detail by electron microscopy. In general, our in vitro and in vivo results show that virotoxins exhibit the same effect as phalloidin on F actin.

Agaricales↗
PubMed1982

Increased hepatotoxicity of carbon tetrachloride by the hypolipidemic drug nafenopin in rats.

Pretreatment of rats with the potent hypolipidemic drug nafenopin enhanced the hepatotoxicity of carbon tetrachloride as judged by the serum activity of glutamic pyruvic transaminase (SGPT), hepatic triglyceride content and glucose-6-phosphatase activity as well as by light and electronmicroscopy. Nafenopin alone caused an increase in liver weight, proliferation of peroxisomes and of smooth endoplasmic reticulum in hepatocytes. No marked changes of serum SGPT activity were observed, but hepatic glucose-6-phosphatase activity decreased. Results suggest that the hypolipidemic compound can act on endoplasmic reticulum membranes so that they become more susceptible to the attack by carbon tetrachloride or it(s) metabolite(s).

Alanine Transaminase↗
PubMed1981

Changes in liver cell plasma membrane polypeptides of phalloidin-treated rats with special reference to the actomyosin complex.

Studies on isolated liver cell plasma membranes enriched in bile canaliculi from male rats treated with phalloidin show marked changes in the membrane polypeptides. Upon examination by sodium dodecyl sulfate polyacrylamide gel electrophoresis, a protein component identical in mobility to the myosin standard was dramatically reduced, while that corresponding to actin was increased. It is suggested that a myosin-like protein may be necessary for the contractile function of the actin filaments in the liver cells. The observed modifications may be related to the decreased bile secretion and dilatation of bile canaliculi induced by phalloidin.

Actomyosin↗
PubMed1981

Severe familial cholestasis in North American Indian children: a clinical model of microfilament dysfunction?

Studies of 14 North American Indian children with a familial type of severe neonatal cholestasis are described. Jaundice occurred during the neonatal period in 9 children, but disappeared before the end of the 1st yr. Progressive liver damage was documented by the persistence of high levels of alkaline phosphatase, moderate elevation of transaminases, and severe pruritus. Serum bile acids were constantly elevated (3.0-119.5 microgram/ml). Early portal hypertension and variceal bleeding necessitated portal-systemic shunts in 7 children. By light microscopy, the early stage was characterized by hepatitis with giant-cell transformation and biliary stasis. Later on, portal fibrosis became evident and was followed by cirrhosis. By electron microscopy bile canaliculi appeared slightly dilated with preservation or only partial loss of microvilli. They were surrounded by a prominent pericanalicular filamentous web. Immunofluorescence studies indicated the presence of action-containing microfilaments. This group of children might represent a human model of microfilament dysfunction-induced cholestasis.

Actins↗