MECHANISM OF GAMMA-GLUTAMYL TRANSPEPTIDASE RELEASE IN SERUM DURING INTRAHEPATIC AND EXTRAHEPATIC CHOLESTASIS IN THE RAT - A HISTOCHEMICAL, BIOCHEMICAL AND MOLECULAR APPROACH

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.) Copyright © 1990 American Association for the Study of Liver Diseases