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Mitochondrially mediated synergistic cell killing by bile acids
Anabela P Rolo1, Carlos M Palmeira, Kendall B Wallace
1Center for Neurosciences and Cell Biology of Coimbra, Department of Zoology, University of Coimbra, 3004-517, Coimbra, Portugal.
Biochimica Et Biophysica Acta
|January 16, 2003
Summary
Ursodeoxycholate (UDCA) worsens liver injury when combined with chenodeoxycholate (CDCA) in cholestatic liver disease. This synergistic cytotoxicity involves mitochondrial dysfunction and the mitochondrial permeability transition (MPT).
Area of Science:
- Hepatology
- Biochemistry
- Cell Biology
Background:
- Bile acid accumulation causes liver damage in cholestatic liver disease.
- The therapeutic role of ursodeoxycholate (UDCA) in cholestasis is debated.
- Chenodeoxycholate (CDCA) can induce hepatocellular injury.
Purpose of the Study:
- To investigate the effects of UDCA and CDCA on isolated rat hepatocytes.
- To determine if UDCA has cytoprotective or synergistic effects against CDCA-induced injury.
- To elucidate the role of the mitochondrial permeability transition (MPT) in bile acid-induced cytotoxicity.
Main Methods:
- Isolated rat hepatocytes were exposed to UDCA and CDCA.
- Measurements included mitochondrial depolarization, ATP levels, and cell viability.
- The effect of fructose and cyclosporine A (CyA) on bile acid toxicity was assessed.
Main Results:
- UDCA alone was not toxic but potentiated CDCA-induced mitochondrial depolarization, ATP depletion, and cell death.
- Fructose preserved ATP levels and prevented cell killing.
- Cyclosporine A (CyA), an MPT inhibitor, significantly reduced bile acid-induced mitochondrial dysfunction and cell death.
Conclusions:
- UDCA and CDCA exhibit synergistic cytotoxicity against hepatocytes.
- This synergistic effect is mediated by impaired mitochondrial function.
- The mitochondrial permeability transition (MPT) is a key mechanism in UDCA plus CDCA-induced liver injury.