Z Gastroenterol 2009; 47 - A60
DOI: 10.1055/s-0029-1224039

Non-conjugated bile acid induces mitochondrial damage in pancreatic ductal epithelial cell

J Maléth 1, Z Rakonczay 1, V Venglovecz 2, Z Rázga 3, L Tiszlavicz 3, P Hegyi 1
  • 1First Department of Medicine, University of Szeged, Szeged
  • 2Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged
  • 3Department of Pathology, University of Szeged, Szeged

Background: Exposure of the pancreas to bile acids is considered to be one of the possible causes of acute pancreatitis. We have recently shown that a high dose (1 mM) of non-conjugated chenodeoxycholate (CDC) had strong inhibitory effects on the activities of acid/base transporters (Na+/H+ exchanger (NHE), Na+/HCO3- cotransporter (NBC), Cl-/HCO3- exchanger (CBE)) on pancreatic ductal epithelial cells (PDEC). However, the same dose of conjugated glucochenodeoxycholate (GCDC) had no effect on the ion transporters. Our aim was to characterize the intracellular mechanisms of the inhibitory effects of bile acids.

Methods: Intra/interlobular pancreatic ducts were isolated from the pancreas of guinea pig. High dose (1 mM) of CDC or GCDC was administered basolaterally for 1–10 minutes. Intracellular calcium concentration ([Ca2+]i), pH (pHi) and ATP level (ATP)i of PDEC were measured using microfluorometry. Morphological changes of PDEC were evaluated by electron microscopy.

Results: Administration of 1 mM CDC strongly inhibited the acid/base transporters (NHE, NBC and CBE) of PDEC. Neither removal of extracellular Ca2+ nor the Ca2+-chelator BAPTA-AM prevented the inhibitory effects of CDC. GCDC had no effects on the ion transporters. High dose of CDC evoked a toxic sustained [Ca2+]i elevation. Morphological evaluation revealed that high dose of CDC strongly damages the mitochondria. Administration of 1mM CDC for 1min had no effects on the intracellular organelles, however, exposure for 10min killed almost all of the mitochondria. GCDC did not damage the intracellular organelles. Importantly, high dose of CDC decreased the (ATP)i in PDEC.

Conclusion: These results suggest that non-conjugated bile acids damage the mitochondria resulting in a marked ATP depletion of the cell. The lack of ATP will result in a global sustained Ca2+ signal and a total inhibition of NHE, NBC and CBE. Conjugation of bile acids may represent a defence mechanism against the toxicity of bile acids.

This work was supported by OTKA, MTA and NKTH.