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 gamma-glutamyl transpeptidase activity in cholestasis is not clear. We therefore analyzed rat gamma-glutamyl transpeptidase activities in liver, bile and serum during intrahepatic cholestasis induced by a single dose of alpha-naphthyl isothiocyanate (20 mg/100 gm body weight) and during extrahepatic cholestasis after bile duct ligation. At days 1 and 2 after alpha-naphthyl isothiocyanate ingestion, we saw a fivefold and a 60-fold increase in serum and bile gamma-glutamyl transpeptidase activities, respectively. These increases were associated with a decrease in hepatic gamma-glutamyl transpeptidase activity and of corresponding mRNA. Simultaneously, necrosis of the biliary epithelium appeared in portal tracts. From day 2 to day 14, gamma-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 gamma-glutamyl transpeptidase activity and of its corresponding mRNA. In extrahepatic cholestasis, a 10-fold increase in serum gamma-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 gamma-glutamyl transpeptidase activity and in specific mRNA; in bile, gamma-glutamyl transpeptidase activity was slightly elevated. In these two models of cholestasis, histochemically detected gamma-glutamyl transpeptidase activity was largely predominant in biliary cells. We found no significant induction of gamma-glutamyl transpeptidase activity in hepatocytes. These results suggest that in these two models of cholestasis, the increase in serum gamma-glutamyl transpeptidase activity is of biliary cell origin and does not originate from hepatocytes.(ABSTRACT TRUNCATED AT 250 WORDS)
Bulle
F
F
Unité INSERM 99, Hôpital Henri Mondor, Créteil, France.
Mavier
P
P
Zafrani
E S
ES
Preaux
A M
AM
Lescs
M C
MC
Siegrist
S
S
Dhumeaux
D
D
Guellaën
G
G
D015058:1-Naphthylisothiocyanate; D000818:Animals; D001646:Bile / Q000201:enzymology; D001653:Bile Ducts, Intrahepatic / Q000201:enzymology / Q000473:pathology; D001663:Bilirubin / Q000378:metabolism; D015152:Blotting, Northern; D001651:Cholestasis, Extrahepatic / Q000201:enzymology*; D002780:Cholestasis, Intrahepatic / Q000139:chemically induced / Q000201:enzymology*; D003135:Common Bile Duct / Q000601:surgery; D006651:Histocytochemistry; D008026:Ligation; D008099:Liver / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008297:Male; D009336:Necrosis; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D005723:gamma-Glutamyltransferase / Q000097:blood / Q000235:genetics / Q000378:metabolism*
D012333:RNA, Messenger; D015058:1-Naphthylisothiocyanate; D005723:gamma-Glutamyltransferase; D001663:Bilirubin