Chenodeoxycholate is a potent inducer of the permeability transition pore in rat liver mitochondria.
Several reports support the concept that bile acids may be cytotoxic during cholestatic disease process by causing mitochondrial dysfunction. Here we report additional data and findings aimed at a better understanding of the involvement of the permeability transition pore (PTP) opening in bile acids toxicity. The mitochondrial PTP is implicated as a mediator of cell injury and death in many situations. In the presence of calcium and phosphate, chenodeoxycholic acid (CDCA) induced a permeability transition in freshly isolated rat liver mitochondria, characterized by membrane depolarization, release of matrix calcium, and osmotic swelling. All these events were blocked by cyclosporine A (CyA) and the calcium uniporter inhibitor ruthenium red (RR). The results suggest that CDCA increases the sensitivity of isolated mitochondria in vitro to the calcium-dependent induction of the PTP.
Rolo
A P
AP
Center for Neurosciences and Cell Biology of Coimbra, Department of Zoology, University of Coimbra, Portugal.
Oliveira
P J
PJ
Moreno
A J
AJ
Palmeira
C M
CM
D000818:Animals; D002118:Calcium / Q000378:metabolism* / Q000494:pharmacology; D002635:Chenodeoxycholic Acid / Q000633:toxicity*; D002779:Cholestasis / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D016572:Cyclosporine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005765:Gastrointestinal Agents / Q000633:toxicity*; D007202:Indicators and Reagents / Q000494:pharmacology; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D009995:Osmosis / Q000187:drug effects / Q000502:physiology; D010539:Permeability / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012430:Ruthenium Red / Q000494:pharmacology; D013347:Subcellular Fractions
D004791:Enzyme Inhibitors; D005765:Gastrointestinal Agents; D007202:Indicators and Reagents; D002635:Chenodeoxycholic Acid; D012430:Ruthenium Red; D016572:Cyclosporine; D002118:Calcium