Ursodeoxycholic acid prevents cytochrome c release in apoptosis by inhibiting mitochondrial membrane depolarization and channel formation

The hydrophilic bile salt ursodeoxycholic acid (UDCA) is a potent inhibitor of apoptosis, In this paper, we further characterize the mechanism by whic h UDCA inhibits apoptosis induced by deoxycholic acid, okadaic acid and tra nsforming growth factor beta 1 in primary rat hepatocytes. Our data indicat e that coincubation of cells with UDCA and each of the apoptosis-inducing a gents was associated with an approximately 80% inhibition of nuclear fragme ntation (P<0.001), Moreover, UDCA prevented mitochondrial release of cytoch rome c into the cytoplasm by 70-75% (P<0.001), thereby, inhibiting subseque nt activation of DEVD-specific caspases and cleavage of poly(ADP-ribose) po lymerase. Each of the apoptosis-inducing agents decreased mitochondrial tra nsmembrane potential and increased mitochondrial-associated Bar protein lev els. Coincubation with UDCA was associated with significant inhibition of t hese mitochondrial membrane alterations, The results suggest that the mecha nism by which UDCA inhibits apoptosis involves an interplay of events in wh ich both depolarization and channel-forming activity of the mitochondrial m embrane are inhibited.