The non-conjugated chenodeoxycholate induces severe mitochondrial damage and inhibits bicarbonate transport in pancreatic duct cells

Background: We have recently shown that a high contentration (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)) of pancreatic ductal epithelial cells (PDEC). 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 pigs. Intracellular pH (pHi) and ATP level (ATP)i of PDEC were measured using microfluorometry. To investigate the effect of CDC on glycolitic metabolism we used 10 mM deoxyglucose (DOG)/5 mM idoacetamide (IAA). Morphological changes of PDEC were evaluated by transmission electron microscopy.

Results: 1 mM CDC strongly damaged the mitochondria. For positive control we used the mitochondrial toxin CCCP (100µM) which mimicked the effect of CDC. Administration of CDC and/or CCCP markedly and irreversibly reduced (ATP)i. DOG/IAA also decreased (ATP)i. CCCP or DOG/IAA administered after high contentration of CDC resulted in further (ATP)i depletion, however, their effects were significantly smaller after CDC than administered alone. CCCP strongly inhibited NBC, NHE (recovery from acid load) and CBE (recovery from alkali load). Administration of DOG/IAA also inhibited the ion transporters. Significantly higher inhibition was evoked by parallel administration of CCCP and DOG/IAA.

Conclusion: These results suggest that high contentration of the non-conjugated CDC causes mitochondrial damage followed by (ATP)i depletion and CDC inhibits the glycolytic metabolism of PDEC. We showed that the (ATP)i depletion by itself can be responsible for the impaired HCO3- secretion. This work was supported by OTKA, MTA and NKTH.