Original Articles
Chronic administration of omeprazole decreases biliary proliferation of cholestatic rats by increased gastrin serum levels
Abstract
Background: The growth of cholangiocytes following extrahepatic bile duct obstruction (BDL) is coordinately regulated by a number of stimulatory and inhibitory factors. The proton pump inhibitor, omeprazole, exerts a number of functions including: (I) decrease of gastric acid secretion; (II) inhibition of colonic cancer growth; and (III) reduced liver regeneration after partial hepatectomy. The effects of omeprazole are mediated by enhanced gastrin serum levels. Thus, since gastrin inhibit biliary growth, we tested the hypothesis that omeprazole inhibits cholangiocyte proliferation and ductal mass in BDL rats by increasing gastrin serum levels.
Methods: In vivo, male Fischer 344 rats (immediately BDL) were treated with vehicle or omeprazole (40 mg/kg BW by daily gavage administration) for 1 wk. Then, we measured changes in: (I) gastrin serum levels, serum chemistry and intrahepatic bile duct mass in liver sections; (II) H3 histone and PCNA (indices of cell replication) and secretin receptor (SR) gene expression; (III) basal and secretin-stimulated cyclic adenosine 3',5'-monophosphate (cAMP) levels in cholangiocytes bile and bicarbonate secretion in bile fistula rats. Changes in SR and secretin-stimulated secretion are key functional tools for evaluating the degree of biliary hyperplasia.
Results: chronic in vivo administration of omeprazole to BDL rats: (I) increased gastrin serum levels and reduced biliary proliferation and hyperplasia; (II) decreased SR expression and significantly inhibited the stimulatory effects of secretin on cAMP levels and ductal secretion compared to vehicle treated controls. The usage of omeprazole (increasing gastrin serum levels) may be beneficial for the management of chronic cholestatic liver diseases.
Methods: In vivo, male Fischer 344 rats (immediately BDL) were treated with vehicle or omeprazole (40 mg/kg BW by daily gavage administration) for 1 wk. Then, we measured changes in: (I) gastrin serum levels, serum chemistry and intrahepatic bile duct mass in liver sections; (II) H3 histone and PCNA (indices of cell replication) and secretin receptor (SR) gene expression; (III) basal and secretin-stimulated cyclic adenosine 3',5'-monophosphate (cAMP) levels in cholangiocytes bile and bicarbonate secretion in bile fistula rats. Changes in SR and secretin-stimulated secretion are key functional tools for evaluating the degree of biliary hyperplasia.
Results: chronic in vivo administration of omeprazole to BDL rats: (I) increased gastrin serum levels and reduced biliary proliferation and hyperplasia; (II) decreased SR expression and significantly inhibited the stimulatory effects of secretin on cAMP levels and ductal secretion compared to vehicle treated controls. The usage of omeprazole (increasing gastrin serum levels) may be beneficial for the management of chronic cholestatic liver diseases.
