Acute cytotoxic effect of cyclosporin A on pancreatic acinar cells in rats. Protective effect of the synthetic protease inhibitor E3123.
This study was designed to evaluate the acute toxic effects of cyclosporin A on the exocrine pancreas and the protective effects of a new potent protease inhibitor, 4-(2-succinimidoethylthio) phenyl 4-guanidinobenzoate methanesulfonate, E3123. Cyclosporin A in a dose of 5 mg/kg.h caused a significant increase in serum amylase levels, pancreatic amylase content, and interstitial edema, suggesting that it induces exocrine pancreatic injury. Cyclosporin A also caused redistribution of cathepsin B from the lysosomal fraction to the zymogen fraction, indicating colocalization of lysosomal enzymes with pancreatic digestive enzymes. E3123 in a dose of 2 mg/kg.h prevented almost completely these changes caused by cyclosporin A. These results indicate that exocrine pancreatic injury is induced by cyclosporin A and that lysosomal enzymes play important roles in the pathogenesis of this injury and also suggest that E3123 might protect the exocrine pancreas of patients receiving cyclosporin A after organ transplantation.
First Dept. of Surgery, Faculty of Medicine, Kyoto University, Japan.
T
T
Hirano
T
T
Manabe
K
K
Ando
T
T
Tobe
D000681:Amylases / Q000097:blood / Q000187:drug effects; D000818:Animals; D002401:Cathepsin B / Q000187:drug effects / Q000378:metabolism; D016572:Cyclosporine / Q000009:adverse effects* / Q000037:antagonists & inhibitors; D006146:Guanidines / Q000494:pharmacology*; D008297:Male; D010179:Pancreas / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010189:Pancreatic Juice / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*
D006146:Guanidines; D015842:Serine Proteinase Inhibitors; C057059:4-(2-succinimidoethylthio)phenyl 4-guanidinobenzoate; D016572:Cyclosporine; D000681:Amylases; D002401:Cathepsin B