RESUMEN
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.
Asunto(s)
Acetaminofén/toxicidad , Analgésicos no Narcóticos/toxicidad , Colestasis/inducido químicamente , Enfermedades Renales/fisiopatología , Factor de Necrosis Tumoral alfa/fisiología , Alanina Transaminasa/sangre , Animales , Aspartato Aminotransferasas/sangre , Bilirrubina/sangre , Colestasis/fisiopatología , Hígado/efectos de los fármacos , Masculino , Ratas , Ratas Wistar , Factor de Necrosis Tumoral alfa/químicaRESUMEN
Theaim 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.
RESUMEN
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.
Asunto(s)
Acetaminofén/envenenamiento , Analgésicos no Narcóticos/envenenamiento , Colestasis/metabolismo , Glucuronosiltransferasa/metabolismo , Microsomas Hepáticos/metabolismo , Fosfolípidos/metabolismo , Acetaminofén/sangre , Analgésicos no Narcóticos/sangre , Animales , Conductos Biliares/metabolismo , Ligadura , Hígado/efectos de los fármacos , Hígado/patología , Masculino , Microsomas Hepáticos/efectos de los fármacos , Ratas , Ratas WistarRESUMEN
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.
Asunto(s)
Benzodiazepinas/metabolismo , Colestasis/metabolismo , Glucuronosiltransferasa/metabolismo , Hepatopatías/metabolismo , Acetaminofén , Enfermedad Aguda , Analgésicos no Narcóticos , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas , Colestasis/inducido químicamente , Hepatopatías/enzimología , Masculino , Ratas , Ratas WistarRESUMEN
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.
Asunto(s)
Modelos Animales de Enfermedad , Hipertensión Portal , Cirrosis Hepática Experimental , Monocrotalina/farmacología , Venenos/farmacología , Animales , Hipertensión Portal/inducido químicamente , Hipertensión Portal/complicaciones , Hipertensión Portal/fisiopatología , Cirrosis Hepática Experimental/inducido químicamente , Cirrosis Hepática Experimental/complicaciones , Cirrosis Hepática Experimental/fisiopatología , Masculino , Ratas , Ratas WistarRESUMEN
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.
RESUMEN
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.
Asunto(s)
Encéfalo/enzimología , Hipertensión Portal/enzimología , Tirosina 3-Monooxigenasa/metabolismo , Animales , Hipertensión Portal/metabolismo , Masculino , Norepinefrina/biosíntesis , Presión Portal , Ratas , Ratas WistarRESUMEN
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.
Asunto(s)
Glucuronatos/metabolismo , Hipertensión Portal/metabolismo , Inactivación Metabólica/fisiología , Metabolismo de los Lípidos , Microsomas Hepáticos/metabolismo , Nitrofenoles/metabolismo , Animales , Colesterol/metabolismo , Glucuronosiltransferasa/metabolismo , Masculino , Monocrotalina/toxicidad , Fosfolípidos/metabolismo , Ratas , Ratas WistarRESUMEN
The effect of atrial natriuretic factor (ANF) on peritoneal dialysis was studied in bilaterally nephrectomized rats. ANF was injected prior to every dialysis exchange and blood samples were obtained before the instillation of the dialysis solution and during the collection of dialysates. Urea, creatinine, potassium, and sodium were determined in both plasma and dialysates. Results showed that ANF increased the plasma clearance of all studied solutes, probably through vasodilation. Solute clearances showed a gradual increase with each dialysis exchange in both control and experimental animals. Therefore, ANF plasma levels were assayed before, during, and after peritoneal dialysis in a control group of nephrectomized rats to determine whether ANF plasma levels were modified during dialysis. Plasma ANF values were higher during and after peritoneal dialysis, though basal levels were similar to those of non-nephrectomized rats. These results suggest the release of endogenous ANF from the cardiac atria during peritoneal dialysis. The present results suggest that ANF may be of potential interest in the clinical field to increase the efficiency of peritoneal dialysis in man.
Asunto(s)
Factor Natriurético Atrial/farmacología , Diálisis Peritoneal , Animales , Factor Natriurético Atrial/administración & dosificación , Factor Natriurético Atrial/sangre , Creatinina/metabolismo , Soluciones para Diálisis , Masculino , Nefrectomía , Potasio/metabolismo , Ratas , Ratas Wistar , Sodio/metabolismo , Urea/metabolismoRESUMEN
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.
Asunto(s)
Acetaminofén/envenenamiento , Analgésicos no Narcóticos/envenenamiento , Enfermedad Hepática Inducida por Sustancias y Drogas , Colestasis/inducido químicamente , Hígado/efectos de los fármacos , Acetaminofén/metabolismo , Analgésicos no Narcóticos/metabolismo , Animales , Sobredosis de Droga , Hepatopatías/metabolismo , Masculino , Ratas , Ratas WistarRESUMEN
Phospholipid fatty acid composition and bilirubin UDP-glucuronyltransferase activity from liver microsomal membrane were studied in normal and in bile duct ligated rats. Incubation of normal microsomes with 15 microM bilirubin (considered as physiological concentration) yielded 60% bilirubin diglucuronide; in 2 days post-cholestatic rats, they showed 20% bilirubin diglucuronide which was undetectable in 8 days post-cholestatic group. When compared to controls, after 2 days of cholestasis, microsomal phospholipids showed a clear decrease in linoleic and arachidonic acids and an increment in palmitic and stearic acids. 8 days post-cholestatic rats presented a marked increase in palmitic, oleic and docosaexaenoic acids, while linoleic and arachidonic acids decreased. Cholestasis produced disturbances in microsomal phospholipids fatty acid composition; but these changes are unable to explain entirely the severe damage observed in bilirubin diglucuronide formation.
Asunto(s)
Colestasis/metabolismo , Ácidos Grasos/análisis , Glucuronosiltransferasa/metabolismo , Microsomas Hepáticos/metabolismo , Fosfolípidos/química , Animales , Colestasis/enzimología , Constricción , Masculino , Ratas , Ratas WistarRESUMEN
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.
Asunto(s)
Acetaminofén/toxicidad , Colestasis Extrahepática/inducido químicamente , Acetaminofén/administración & dosificación , Acetaminofén/metabolismo , Enfermedad Aguda , Animales , Colestasis Extrahepática/enzimología , Sobredosis de Droga , Glucuronosiltransferasa/metabolismo , Hígado/efectos de los fármacos , Hígado/enzimología , Hígado/patología , Masculino , Ratas , Ratas WistarRESUMEN
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.
RESUMEN
Liver microsomal glucuronidation of acetaminophen, chloramphenicol, salicylic acid, lorazepam, p-nitrophenol and morphine were measured in 8 days bile duct ligated rats. Compared to normals, cholestatic rats showed a decrease of 31% for p-nitrophenol glucuronidation; salicylic acid glucuronidation increased 281%; acetaminophen glucuronidation increased 38% while morphine, chloramphenicol and lorazepam values were similar to controls. We concluded that cholestasis produces non predictable changes on liver drug glucuronidation pathways.
Asunto(s)
Colestasis/metabolismo , Glucuronatos/metabolismo , Microsomas Hepáticos/metabolismo , Preparaciones Farmacéuticas/metabolismo , Acetaminofén/metabolismo , Animales , Cloranfenicol/metabolismo , Glucuronosiltransferasa/metabolismo , Lorazepam/metabolismo , Masculino , Morfina/metabolismo , NAD/metabolismo , Nitrofenoles/metabolismo , Ratas , Ratas Wistar , Salicilatos/metabolismo , Ácido SalicílicoRESUMEN
Liver microsomal glucuronidation of p-nitrophenol was measured in normal, 2 and 8 day bile duct ligated rats. At low aglycone concentration (0.24-0.8 mM) a Michaelis-Menten kinetic was registered in the three groups of animals but cholestatic rats showed a decrease of activity related to the time that cholestasis was maintained. At higher substrate concentration (1.2-2.0 mM), a very different behavior between the three groups was observed: normal rats showed a substrate inhibition phenomena; 2 day rats maintained plateau values and a remarkable activation effect of the activity was seen in the 8 day group. We concluded that cholestasis produced pronounced changes in p-nitrophenol glucuronidation pathway.
Asunto(s)
Colestasis/metabolismo , Glucuronosiltransferasa/metabolismo , Microsomas Hepáticos/metabolismo , Nitrofenoles/metabolismo , Animales , Cinética , Masculino , Ratas , Ratas WistarRESUMEN
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.
Asunto(s)
Acetaminofén/metabolismo , Colestasis Extrahepática/metabolismo , Glucuronosiltransferasa/metabolismo , Animales , Ácidos Grasos/química , Masculino , Microsomas Hepáticos/metabolismo , Fosfolípidos/química , Ratas , Ratas WistarRESUMEN
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.
RESUMEN
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.
RESUMEN
In the rat, the effect of the bile duct ligation on liver microsomal phospholipid fatty acid composition and on phosphatidylcholine, phosphatidylserine and phosphatidylinositol pattern were studied. After two days of cholestasis, microsomal phospholipid fatty acids showed a decrease in linoleic, stearic and arachidonic acids and an increase in oleic and docosahexaenoic ones, as compared to controls. Phosphatidylcholine showed an increment in oleic and palmitic acid content and a concomitant decrease in arachidonic acid. Phosphatidylserine showed a progressive increase while phosphatidylinositol showed a progressive decrease in all fatty acids. Eight-days post-cholestatic rats showed a marked increase in oleic acid, whereas linoleic, arachidonic, stearic and palmitic acids concentration decreased. Phosphatidylcholine showed a global decrease in its fatty acid content, except for oleic which is increased. Phosphatidylserine showed an increase over the two-days cholestasis fatty acids values. Phosphatidylinositol decreased in most fatty acids except in docosahexaenoic acid that recovered normal values. It was concluded that cholestasis produced significative changes in the fatty acid composition of the major phospholipids constituents of the microsomal membranes.
Asunto(s)
Colestasis Extrahepática/metabolismo , Ácidos Grasos/metabolismo , Microsomas Hepáticos/metabolismo , Fosfolípidos/metabolismo , Animales , Ácido Araquidónico/metabolismo , Ácido Linoleico , Ácidos Linoleicos/metabolismo , Masculino , Ácido Oléico , Ácidos Oléicos/metabolismo , Ácido Palmítico , Ácidos Palmíticos/metabolismo , Fosfatidilcolinas/metabolismo , Fosfatidilinositoles/metabolismo , Fosfatidilserinas/metabolismo , Ratas , Ratas Endogámicas , Ácidos Esteáricos/metabolismoRESUMEN
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.