Mechanism of γ-glutamyl transpeptidase release in serum during intrahepatic and extrahepatic cholestasis in the rat: A histochemical, biochemical and molecular approach

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Abstract

The mechanism of the elevation of serum γ-glutamyl transpeptidase activity in cholestasis is not clear. We therefore analyzed rat γ-glutamyl transpeptidase activities in liver, bile and serum during intrahepatic cholestasis induced by a single dose of α-naphthyl isothiocyanate (20 mg/100 gm body weight) and during extrahepatic cholestasis after bile duct ligation. At days 1 and 2 after α-naphthyl isothiocyanate ingestion, we saw a fivefold and a 60-fold increase in serum and bile γ-glutamyl transpeptidase activities, respectively. These increases were associated with a decrease in hepatic γ-glutamyl transpeptidase activity and of corresponding mRNA. Simultaneously, necrosis of the biliary epithelium appeared in portal tracts. From day 2 to day 14, γ-glutamyl transpeptidase activity in bile and serum progressively returned to basal levels; in the liver, cholangiolar proliferation was mild and was associated with moderate elevation of the γ-glutamyl transpeptidase activity and of its corresponding mRNA. In extrahepatic cholestasis, a 10-fold increase in serum γ-glutamyl transpeptidase activity was detected between day 0 and day 14. This increase was associated with major cholangiolar proliferation and with a progressive rise in hepatic γ-glutamyl transpeptidase activity and in specific mRNA; in bile, γ-glutamyl transpeptidase activity was slightly elevated. In these two models of cholestasis, histochemically detected γ-glutamyl transpeptidase activity was largely predominant in biliary cells. We found no significant induction of γ-glutamyl transpeptidase activity in hepatocytes. These results suggest that in these two models of cholestasis, the increase in serum γ-glutamyl transpeptidase activity is of biliary cell origin and does not originate from hepatocytes. This mechanism is quite different from the hepatocyte inductionhypothesized for alkaline phosphatase.(HEPATOLOGY 1990; 11:545:550.)

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