Graciela Ouviña

Protein and lipid disturbances in rat liver microsomal membranes after bile duct ligation

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.

Liver microsomal bilirubin UDP-Glucuronyltransferase disturbances in bile duct ligated rats

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.

Cholestasis as a liver protective factor in paracetamol acute overdose

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.

Changes in liver drug glucuronidation during cholestasis are non predictable

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.

Changes in microsomal phospholipid fatty acids composition in cholestatic rats

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.

p-nitrophenol glucuronidation in bile duct ligated rats

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.