Do intracellular Ca2+ activity and hepatic glutathione play a role in the pathogenesis of lithocholic acid-induced cholestasis?
The possible relevance of alterations in intracellular Ca2+ and hepatic glutathione levels (GSH) in the pathogenesis of cholestasis induced by lithocholic acid (LCA) was examined by comparing effects of LCA and acetaminophen on these parameters and bile flow (BF) in rats. Intracellular Ca2+ activity was measured via glycogen phosphorylase a determination in rats given an intravenous bolus injection of either LCA (12 mumol/100 g body wt.), acetaminophen (60 mg/100 g body wt.), or a mixed solution of LCA and acetaminophen. BF was reduced immediately after LCA administration, with a maximum decrease occurring at 60 min followed by an increase to normal values at 210 min. On the other hand, glycogen phosphorylase a activity was elevated during all time periods after LCA treatment. Hepatic glutathione followed the BF curves being markedly depleted at the peak of cholestasis (60 min) and normal in the total recovery period (210 min). In contrast, acetaminophen had no effect on BF but significantly increased glycogen phosphorylase a activity and depleted hepatic glutathione levels. These results suggest that cholestatic effect of LCA is not due to changes in intracellular Ca2+ or hepatic glutathione levels.
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Department of Pharmacology and Nutrition, Université de Montréal, Québec, Canada.
Tuchweber
B
B
Plaa
G L
GL
Yousef
I M
IM
D000082:Acetaminophen / Q000633:toxicity; D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000502:physiology*; D002779:Cholestasis / Q000209:etiology*; D004357:Drug Synergism; D005978:Glutathione / Q000502:physiology*; D007275:Injections, Intravenous; D008095:Lithocholic Acid / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D006005:Phosphorylases / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
D000082:Acetaminophen; D008095:Lithocholic Acid; D006005:Phosphorylases; D005978:Glutathione; D002118:Calcium