Effects of acute pancreatitis on hepatic secretion of lysosomal enzymes into bile and hepatic lysosomal fragility: protective effects of a new synthetic protease inhibitor, ONO 3307.
To evaluate the effects of acute pancreatitis on hepatic function and hepatic cellular and subcellular organellar fragility, we studied 1) the hepatic secretion of lysosomal enzymes (beta-glucuronidase, beta-galactosidase, and N-acetyl-beta-glucosaminidase) into bile in the isolated perfused rat liver model; 2) the aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), and lysosomal enzyme levels in the effluent in an isolated liver model; 3) hepatic lysosomal fragility in an in vitro incubation study; and 4) protective effects of a new low molecular weight synthetic protease inhibitor, ONO 3307, against hepatic injury in doses of 2 and 5 mg/kg.h in acute pancreatitis induced by a supramaximal dose of cerulein in rats. Decreased hepatic secretion of lysosomal enzymes into bile and accelerated hepatic lysosomal fragility were observed in acute pancreatitis induced by cerulein. ONO 3307 showed a significant protective effect against this hepatic injury in acute pancreatitis, the dose of 5 mg/kg.h showing a more potent effect than the dose of 2 mg/kg.h. These results suggest that the impaired hepatic function, including depressed hepatic secretion of lysosomal enzymes, seems to be closely related to accelerated hepatic fragility and that some unknown protease, which is present in pancreatitis and is susceptible to inhibition by ONO 3307, plays a crucial pathologic role in the development of this liver injury during acute pancreatitis.
Hirano
T
T
Dept. of Surgery, Addenbrooke's Hospital, Cambridge, U.K.
Manabe
T
T
Calne
R
R
Tobe
T
T
D000208:Acute Disease; D000818:Animals; D001646:Bile / Q000201:enzymology*; D006146:Guanidines / Q000627:therapeutic use*; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008247:Lysosomes / Q000201:enzymology; D008297:Male; D010195:Pancreatitis / Q000188:drug therapy / Q000503:physiopathology*; D010477:Perfusion; D051381:Rats; D011919:Rats, Inbred Strains; D015842:Serine Proteinase Inhibitors / Q000627:therapeutic use*
D006146:Guanidines; D015842:Serine Proteinase Inhibitors; C062836:ONO 3307