Ursodeoxycholic acid

Gastroenterology. 2003 Apr;124(4):889-93.

Ursodeoxycholic acid as a chemopreventive agent in patients with ulcerative colitis and primary sclerosing cholangitis.[Pubmed: 12671884 ]

Ursodeoxycholic acid (UDCA) has shown effectiveness as a colon cancer chemopreventive agent in preclinical studies. In addition, a recent report suggests that it also may decrease the risk for developing colorectal dysplasia in patients with ulcerative colitis (UC) and primary sclerosing cholangitis (PSC). We sought to evaluate the effect of UDCA on colorectal neoplasia in a group of patients with UC and PSC enrolled in a randomized, placebo-controlled trial.
METHODS AND RESULTS:
From a prior, randomized, placebo-controlled trial of UDCA therapy in PSC at our center, we followed-up patients with concomitant UC to assess the effect of UDCA on the development of colorectal dysplasia and cancer as compared with placebo. Fifty-two subjects were followed-up for a total of 355 person-years. Those originally assigned to receive UDCA had a relative risk of 0.26 for developing colorectal dysplasia or cancer (95% confidence interval, 0.06-0.92; P = 0.034). Many of the patients originally assigned to the placebo group eventually received open-label UDCA. Assigning these patients to the UDCA group from the time they began active therapy did not change the magnitude of the protective effect (relative risk, 0.26; 95% confidence interval, 0.07-0.99; P = 0.049).
CONCLUSIONS:
UDCA significantly decreases the risk for developing colorectal dysplasia or cancer in patients with UC and PSC.

Dig Dis Sci. 2004 Oct;49(10):1569-74.

Ursodeoxycholic acid ameliorates experimental ileitis counteracting intestinal barrier dysfunction and oxidative stress.[Pubmed: 15573906]

The aim of this study was to evaluate the effect of Ursodeoxycholic acid (UDCA) on intestinal permeability (IP) and reactive oxygen species (ROS) generation in indomethacin-induced enteropathy, a well-known experimental model of Crohn's disease.
METHODS AND RESULTS:
Seventy-eight male Wistar rats were randomly assigned to receive indomethacin, indomethacin + UDCA, or vehicles. Indomethacin induced a significant increase in the fraction of urinary excretion of 51Cr-EDTA following oral administration (7.9 +/- 1.3 vs 2.3 +/- 0.2%; P < 0.05) and lucigenin-amplified chemiluminescence in intestinal fragments ex vivo (10.1 +/- 1.9 vs 2.6 +/- 0.4 cpm x 10(3)/mg; P < 0.05) compared to controls. UDCA significantly reversed these effects (P < 0.05), without being incorporated in biliary bile acid composition (HPLC analysis).
CONCLUSIONS:
These findings support a local protective effect of UDCA in experimental ileitis by the modulation of intestinal barrier dysfunction and oxidative stress. In short, they provide insights into mechanisms of action of UDCA in intestinal inflammation and a new perspective on the treatment of Crohn's disease.

Cell Death Differ. 1999 Sep;6(9):842-54.

Ursodeoxycholic acid prevents cytochrome c release in apoptosis by inhibiting mitochondrial membrane depolarization and channel formation.[Pubmed: 10510466 ]

The hydrophilic bile salt Ursodeoxycholic acid (UDCA) is a potent inhibitor of apoptosis.
METHODS AND RESULTS:
In this paper, we further characterize the mechanism by which UDCA inhibits apoptosis induced by deoxycholic acid, okadaic acid and transforming growth factor beta1 in primary rat hepatocytes. Our data indicate that coincubation of cells with UDCA and each of the apoptosis-inducing agents was associated with an approximately 80% inhibition of nuclear fragmentation (P<0.001). Moreover, UDCA prevented mitochondrial release of cytochrome c into the cytoplasm by 70 - 75% (P<0.001), thereby, inhibiting subsequent activation of DEVD-specific caspases and cleavage of poly(ADP-ribose) polymerase. Each of the apoptosis-inducing agents decreased mitochondrial transmembrane potential and increased mitochondrial-associated Bax protein levels. Coincubation with UDCA was associated with significant inhibition of these mitochondrial membrane alterations.
CONCLUSIONS:
The results suggest that the mechanism by which UDCA inhibits apoptosis involves an interplay of events in which both depolarization and channel-forming activity of the mitochondrial membrane are inhibited.

Gastroenterology. 2002 Oct;123(4):1238-51.

Ursodeoxycholic acid aggravates bile infarcts in bile duct-ligated and Mdr2 knockout mice via disruption of cholangioles.[Pubmed: 12360485]

The effects of Ursodeoxycholic acid (UDCA) in biliary obstruction are unclear. We aimed to determine the effects of UDCA in bile duct-ligated and in Mdr2 knockout (Mdr2(-/-)) mice with biliary strictures.
METHODS AND RESULTS:
Mice fed UDCA (0.5% wt/wt) or a control diet were subjected to common bile duct ligation (CBDL), selective bile duct ligation (SBDL), or sham operation. UDCA was also fed to 2-month-old Mdr2(-/-) mice. Serum biochemistry, liver histology, and mortality rates were investigated. The biliary tract was studied by plastination, India ink injection, and electron microscopy. The effects of UDCA on biliary pressure were determined by cholangiomanometry. UDCA feeding in CBDL mice increased biliary pressure, with subsequent rupture of cholangioles and aggravation of hepatocyte necroses, resulting in significantly increased mortality. UDCA feeding in SBDL mice aggravated liver injury exclusively in the ligated lobe. Mdr2(-/-) mice developed liver lesions resembling sclerosing cholangitis characterized by biliary strictures and dilatations. UDCA induced bile infarcts in these animals.
CONCLUSIONS:
UDCA aggravates bile infarcts and hepatocyte necroses in mice with biliary obstruction via disruption of cholangioles as a result of increased biliary pressure caused by its choleretic action.