ToxSci Advance Access originally published online on February 19, 2004
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Toxicological Sciences 79, 196-204 (2004)
Toxicological Sciences vol. 79 no. 1 © Society of Toxicology; all rights reserved.
Role of Mitochondrial Dysfunction in Combined Bile Acid–Induced Cytotoxicity: The Switch Between Apoptosis and Necrosis
,1
* Center for Neurosciences and Cell Biology of Coimbra, Department of Zoology, University of Coimbra, 3004–517 Coimbra, Portugal; Department of Anatomy and Cell Biology, University of Minnesota School of Medicine, 1035 University Drive, Duluth, Minnesota 55812; and Department of Biochemistry and Molecular Biology, University of Minnesota School of Medicine, 1035 University Drive, Duluth, Minnesota 55812
Received November 26, 2003; accepted January 20, 2004
The goal of this investigation was to determine whether chenodeoxycholic acid (CDCA)-induced apoptosis is prevented by ursodeoxycholic acid (UDCA) or tauroursodeoxycholic acid (TUDC) and to characterize the involvement of mitochondria in the process. Cultured human HepG2 cells were treated in a dose- and time-dependent protocol in order to establish a sufficiently low exposure to CDCA that causes apoptosis but not necrosis. Low-dose CDCA induced an S-phase block and G2 arrest of the cell cycle, as determined by flow cytometry. As a result, cell proliferation was inhibited. CDCA-induced apoptosis, as determined by fluorescence microscopy of Hoechst 33342-stained nuclei, was evident upon coincubation with TUDC. Additionally, after exposure to UDCA plus CDCA, the cell membrane was permeable to fluorescent dyes. Caspase-9-like activity, poly(ADP-ribose) polymerase (PARP) cleavage, and extensive DNA fragmentation were detected in CDCA-exposed cells and in cells coincubated with TUDC, but not UDCA. CDCA caused a decrease in mitochondrial membrane potential and depletion of ATP, both of which were potentiated by UDCA but not TUDC. The results suggest that UDCA potentiates CDCA cytotoxicity, probably at the level of induction of the mitochondrial permeability transition (MPT). Consequently, as suggested by the lack of the main hallmarks of the apoptotic pathway, in the presence of UDCA, CDCA-induced apoptosis is not properly executed but degenerates into necrosis.
Key Words: chenodeoxycholic acid; ursodeoxycholic acid; combination; apoptosis; necrosis; mitochondria.
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