Biomedical subjects
Publications and source records attributed to L Bengochea.
The aim of the present paper is to establish the possible role of serum TNF in the pathophysiology of three experimental models of liver injury: paracetamol intoxication, cholestasis followed by paracetamol intoxication and cholestasis. We concluded that under our experimental conditions the serum TNF-alpha levels were not responsible for the inflammatory phenomena described in our previous paper as apoptosis.
The uridin-diphosphoglucuronyl-transferase (UDP-GT) is a membrane-bound enzyme responsible for glucuronidation of endogenous and exogenous compounds. This work established the UDP-GT activity and its lipid membrane microenvironment in two experimental models: acute paracetamol intoxication, and cholestasis followed by acute paracetamol intoxication. Cholestasis was performed by bile duct ligation. After 7 days animals were injected with paracetamol (BDL-APAP group). Sham-operated rats were injected at day 7 with paracetamol (APAP group). Cholestatic and sham-operated rats injected with vehicle (BDL and control groups). UDP-GT activity was measured by a kinetic method for different substrates. Microsomal membrane phospholipid composition, cholesterol content and ultrastructure were determined. BDL-APAP group showed an increment in the UDP-GT activity except for chloramphenicol, morphine and paracetamol if compared to controls and to BDL group. The same increment was observed when BDL-APAP was compared to APAP except for chloramphenicol and lorazepam. Between BDL and APAP groups similar levels of activity were detected except for paracetamol. Microsomal phospholipid profile: phosphatidylcholine showed the lowest content in the BDL group, with a significant recovery in the BDL-APAP and APAP groups. Phosphatidylserine was markedly decreased in the APAP group compared to the rest and phosphatidylinositol was decreased in all the groups if compared to control values. An increment of phosphatidylethanolamine was seen in the APAP and BDL-APAP groups if compared to BDL and control values. A significant increment of microsomal cholesterol content was seen in BDL. Under these conditions, a different lipid microenvironment is produced, resulting in an increment of the enzyme activity for a variety of substrates.
The aim of the present paper is to establish possible disturbances in benzodiazepines glucuronidation in two experimental models of liver injury: paracetamol acute intoxication and cholestasis followed by paracetamol acute intoxication. We concluded that, despite the alterations observed in liver microsomal lipid profile, glucuronidation remained similar to controls in paracetamol intoxicated rats. On the contrary, cholestatic animals followed by paracetamol intoxication showed an increment in the glucuronidation of the utilized substrated.
The liver is responsible for the most important metabolic pathway of non polar compounds. The aim of the present work was to study the p-nitrophenol glucuronidation and its relationship with lipidic composition of microsomal membrane in a model of hepatic portal hypertension and hepatocellular damage induced by monocrotaline. A global increment in liver microsomal phospholipids as well as changes in the phospholipid pattern (phosphatidylethanolamine and sphingomyelin increased up to 156 +/- 13 and 195 +/- 14% respectively) were detected in monocrotaline intoxicated rats when it were compared to control rats. The microsomal cholesterol content showed a decrease in monocrotaline intoxicated rats. (4.1 +/- 0.7 against 6.6 +/- 1.5 micrograms/mg of microsomal protein, in control rats). When p-nitrophenol activity was measured, Km from monocrotaline intoxicated rats was 0.137 mM, and Vmax was 2.9 nmol of p-nitrophenol/mg microsomal protein since in control group Km was 0.322 mM, and Vmax was 4.5 nmol of p-nitrophenol/mg microsomal protein. It is concluded that monocrotaline intoxicated rats showed a different behavior in the kinetics of p-nitrophenol UDP-glucuronyltransferase, as well as a different microsomal lipidic profile, when compared to control group.
1. The effect of paracetamol overdoses on its disposition was investigated in cholestatic rats. 2. Paracetamol plasma concentration and hepatic accumulation decrease about 70-80% in cholestatic rats. 3. Cholestatic rats intoxicated with paracetamol showed less hepatic damage as concluded from biochemical and histological findings. These data are correlated with liver and plasmatic paracetamol. 4. These results indicate a decrease in paracetamol toxicity related to stagnant bile.
The aim of the present paper is to determine the effect of Paracetamol (P) acute intoxication in cholestatic rats. Four groups of animals were considered: controls, controls intoxicated with P, rats intoxicated with P and cholestatic rats. Hepatic biochemical tests and liver histology were performed in every group. It is concluded that cholestatic rats intoxicated with P showed less Liver damage than in control groups.
Acetaminophen glucuronidation ability and its relationship to hepatic microsomal phospholipid changes were studied during experimental extrahepatic cholestasis. This study included two groups of Wistar rats: 1) normal rats and 2) cholestatic rats. UDP-Glucuronyltransferase activity (UDP-GT) towards acetaminophen resulted increased in 38% (p < 0.05) in the cholestatic group when compared to normal rats. We also found important changes in hepatocyte microsomal phospholipid profile. When phosphatidylcholine fatty acid composition was analysed, all of them resulted diminished except for an increment on oleic acid content (36%). This fatty acid increase in the main membrane phospholipid had a parallel behaviour with acetaminophen glucuronidation activity. This fact could support an activation role for oleic acid over this enzymic system.
The aim of the present study was to determine the effect of bile flow impairment on hepatic lorazepam detoxication and its relationship with the liver microsomal membrane phospholipid composition. It was observed a decrease of phosphatidylcholine, phosphatidylinositol, phosphatidylethanolamine and sphingomyelin content and an increase of phosphatidylserine and phosphatidylglycerol. A similar activity on lorazepam detoxication was observed when cholestatic rats were compared to controls. These results suggest that there is a different modulation than the phospholipid environment play the key role in lorazepam metabolism, independently of membrane.
The effect of aging on hepatic microsomal membrane phospholipid composition was studied composition was studied in both young (2 months) and mature (6 months) Wistar rats. When total microsomal phospholipid content was analysed the aged group showed a significant increment (73%). Microsomal phospholipid pattern also showed a different behavior between both groups, with a significative increase in phosphatidylcholine (62%), phosphatidylserine (124%), phosphatidylinositol (31%) and sphingomyelin (10%) and appearance of phosphatidylethanolamine and phosphatidylglycerol in the six-month group. A higher microsomal membrane fluidity in the aged animals was revealed by the increase in PC/EM index (47%). This increment jin fluidity during aging process may reflect an adaptative response resulting in changes on the enzyme activities responsible for drug and carcinogen metabolism.
A number of morphological and functional changes on liver cells were reported during experimental cholestasis. Some specific metabolic pathways catalyzed by "membrane bound" enzymes were described to be altered by lipid microenvironment changes. The purpose of he present study is to establish Bilirubin UDP-Glucuronyltransferase activity--a microsomal integral enzyme responsible for bilirubin conjugation--and microsomal phospholipid profile in cholestatic and normal patients. Surgical liver biopsies were taken fron five patients suffering prolonged extrahepatic cholestasis, and five patients submitted to abdominal surgery excluding hepato-biliary diseases that were considered as controls. The following biochemical parameters were determined in both groups: bilirubin concentration, alkaline phosphatase, gamma-glutamyltranspeptidase, oxalacetic and pyruvic transaminases, and pseudo-cholinesterase activities. Serum cholestatic markers showed significative increments in cholestatic patients (Table 1). Total Bilirubin UDP-Glucuronyltransferase activity was similar comparing normal and cholestatic individuals (1.11 +/- 0.66 and 1.93 +/- 0.82 nmol conjugated bilirubin/mg protein in 10 min. respectively). When final reaction product was analysed, the normal group showed 80% of bilirubin diglucuronide; but resulted undetectable in cholestatic patients yielding 100% of bilirubin monoglucuronide. Microsomal phospholipid analysis showed a decrease in phosphatidylcholine and phosphatidylethanolamine contents in the cholestatic group; probably due to the action of bile acids accumulated into the hepatic cells. Simultaneously we found an increment in phosphatidylserine and sphingomyelin levels in cholestatic patients compared to normals (Figure 1). This fact could be explained by the existence of special sites in the membrane for the latter phospholipids, protected against bile acids detersive action.(ABSTRACT TRUNCATED AT 250 WORDS)
An analysis of proteins, phospholipids and cholesterol from liver microsomal membranes was performed in normal and post-cholestatic rats. Bile duct ligated rats showed a progressive decrease of these membrane constituents. Minor changes in peptide analysis, a marked decrease of phosphatidylcholine and phosphatidylinositol, disappearance of phosphatidylethanolamine and sphingomyelin, and a clear increment of phosphatidylserine was observed in post-cholestatic as compared to normal group. It was concluded that extra-hepatic cholestasis produces structural changes on the liver microsomes, particularly on phospholipid profile.
The activity of bilirubin UDP-Glucuronyltransferase was determined in microsomes from normal and bile duct ligated rats. It was measured after 2 and 8 days following bile duct ligation and compared with normal rats. A decrease of 33% in the total enzyme activity was observed on day 2; a fall of 70% was founded on day 8. Bilirubin diglucuronide represented approximately 20% of total conjugates in both groups of cholestatic rats, as compared with 65% found in normals. It was concluded that bilirubin microsomal conjugating capacity is markedly altered during cholestasis. This can be attributed to microsomal membrane damage produced by stagnant bile.
Twenty patients with severe hepatic failure and fatal evolution, in whom hemostatic parameters were studied are presented. Eleven had fulminant acute viral hepatitis (FVH) and nine had liver cirrhosis. Hepatic parenchymal failure was followed by altered coagulation factors. In FVH major disturbances were detected in factors II, V, VII - X. In our cirrhotic patients factor alterations were moderated. In spite of these differences the percentage of bleeding patients was similar in both groups. Prothrombin time plus tromboplastine partial time (KPTT) are useful prognostic complements for these two entities.
Serum creatine kinase isoenzymes were determined in 24 patients with hepatic failure. Hepatic failure was due to severe acute and chronic liver disease. The 24 patients presented different degrees of coma. Nineteen cases (seven hepatitis and 12 cirrhosis) in coma grades III and IV showed the presence in serum of BB, brain and MB, myocardial isoenzymes. Follow up in six of these cases demonstrated that worsening or improvement was accompanied by an increase or decrease of this brain isoenzyme concentration. The leakage from their respective tissues of the brain and myocardial creatine kinase isoenzymes is probably due to the toxic and surface activity properties of serum free fatty acids, bile salts, and bilirrubin, which increase, among other factors, in these pathological entities.
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BACKGROUND/AIMS: Hepatic cirrhosis accompanied by portal hypertension is a common cause of death in human beings. The aim of the present study was to develop an experimental model of hepatic portal hypertension associated with liver damage. METHODOLOGY: To develop liver damage in rats, we used the toxic alkaloid monocrotaline. Two groups of male Wistar rats were used. Group 1 was injected with a single dose of monocrotaline (60 mg/kg of body weight) intraperitoneally. Group 2 was injected with an equal volume of saline solution. After 44 days, the animals underwent the following tests: splenoportography and measurement of portal pressure, hepatic serum biochemical tests, and light and electron microscopy. RESULTS: Group 1 showed a significant increase in splenic pressure, superior and inferior collateral circulation, and an increase in portal vein diameter. Serious alterations were detected in hepatic serum markers. Light microscopy showed different degrees of hepatocyte damage, varying from edema to focal necrosis. Ultrastructural changes were of membrane disruption, mitochondrial and nuclear alterations. CONCLUSIONS: The present experimental model could be useful in establishing the pathophysiological changes associated with portal hypertension due to liver damage.
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BACKGROUND/AIMS: Portal hypertension in patients and rat models are characterized by splanchnic and systemic hemodynamic alterations. Both the central and autonomic nervous systems are implicated in its pathophysiology. The aim of our research was to study the tyrosine hydroxylase activity and the rate limiting step in the biosynthesis of catecholamines in partial ligated portal hypertensive and in control rat brains. METHODOLOGY: The following seven discrete brain regions were investigated: Subfornical Organ, Organum Vasculosum Lamina Terminalis, Median Eminence, Periventricular Nucleus, Area Postrema, Locus Coeruleus and Nucleus Tractus Solitarius. RESULTS: The enzyme activity showed a significant increment in six nuclei and a decrease in Area Postrema Nucleus when portal hypertensive rats were compared to controls. CONCLUSIONS: These results suggest the participation of some discrete brain regions in the mechanism of hepatic portal hypertension under the present rat model.