Is ursodeoxycholic acid an effective treatment for primary biliary cirrhosis

Ursodeoxycholic acid ‘mechanisms of action and clinical use in hepatobiliary disorders’

Induction of Liver Growth by Xenobiotic Compounds and Other Stimuli

https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep.24229

Drug‐induced cholestasis

The hydrophilic bile salt ursodeoxycholate (UDCA) inhibits injury by hydrophobic bile acids and is used to treat cholestatic liver diseases. Interestingly, hepatocyte cell death from bile acid-induced toxicity occurs more frequently from apoptosis than from necrosis. However, both processes appear to involve the mitochondrial membrane permeability transition (MPT). In this study, we determined the inhibitory effect of UDCA on deoxycholic acid (DCA)-induced MPT in isolated mitochondria by measuring changes in transmembrane potential (ΔΨm) and production of reactive oxygen species (ROS). In addition, we examined the expression of apoptosis-associated proteins in mitochondria isolated from livers of bile acid-fed animals. Adult male rats were maintained on standard diet supplemented with DCA and/or UDCA for 10 days. Mitochondria were isolated from livers by sucrose/percoll gradient centrifugation and MPT was measured using spectrophotometric and fluorimetric assays. ΔΨm and ROS generation were determined by FACScan analysis. Cytoplasmic and mitochondrial protein abundance were determined by Western blot analysis. DCA increased mitochondrial swelling 25-fold over controls (p 40% (p < 0.001). Similarly, UDCA inhibited DCA-mediated release of calcein-loaded mitochondria by 50% (p < 0.001). ΔΨm was significantly decreased in mitochondria incubated with DCA but not with UDCA. ΔΨm disruption was followed closely by increased superoxide anion and peroxides production (p < 0.01). Coincubation of mitochondria with UDCA significantly inhibited the changes associated with DCA (p < 0.05). In vivo, DCA feeding was associated with a 4.5-fold increase in mitochondria-associated Bax protein levels (p < 0.001); combination feeding with UDCA almost totally inhibited this increase (p < 0.001). UDCA significantly reduces DCA-induced disruption of ΔΨm, ROS production, and Bax protein abundance in mitochondria, suggesting both short- and long-term mechanisms in preventing MPT. The results suggest a possible role for UDCA as a therapeutic agent in the treatment of both hepatic and nonhepatic diseases associated with high levels of apoptosis.

/pdf/ursodeoxycholic-acid-may-inhibit-deoxycholic-acid-induced-544i01wr8y.pdf

Ursodeoxycholic Acid May Inhibit Deoxycholic Acid-Induced Apoptosis by Modulating Mitochondrial Transmembrane Potential and Reactive Oxygen Species Production

Mechanism of Cholestasis: 4. Structural and biochemical changes in the liver and serum in rats after bile duct ligation

Mechanism of cholestasis. 1. Effect of bile acids on microsomal cytochrome P-450 dependent biotransformation system in vitro

Summary In cholestasis, 4 days after bile duct ligation, the activity of aminopyrine demethylase was greatly decreased, while the content of cytochrome P-450 and the activities of aniline hydroxylase, NADPH-cytochrome c reductase, and cytochrome P-450 reductase were only slightly decreased in the microsomes of the rat livers. Binding of type II substrate to cytochrome P-450 was unimpaired and its modifier effect on P-450 reductase was intact. The binding of type I substrate was greatly decreased, and its stimulating effect on P-450 reductase was abolished, suggesting that the effect of cholestasis on the hepatocellular smooth endoplasmic reticulum is to alter the type I binding sites, which is responsible for the hypoactivity of the biotransformation system.

Alteration of microsomal biotransformation in the liver in cholestasis.

Mechanism of cholestasis. 3. Interaction of synthetic detergents with the microsomal cytochrome P-450 dependentbiotransformation system in vitro. A comparison between the effects of detergents, the effects of bile acids, and the findings in bile duct ligated rats.

Paolo G. Bacchin

Papers

Mechanism of Cholestasis: 4. Structural and biochemical changes in the liver and serum in rats after bile duct ligation

Mechanism of cholestasis. 1. Effect of bile acids on microsomal cytochrome P-450 dependent biotransformation system in vitro

Alteration of microsomal biotransformation in the liver in cholestasis.

Mechanism of cholestasis. 3. Interaction of synthetic detergents with the microsomal cytochrome P-450 dependentbiotransformation system in vitro. A comparison between the effects of detergents, the effects of bile acids, and the findings in bile duct ligated rats.

Mechanism of cholestasis. 2. Effect of bile acids on the microsomal electron transfer system in vitro.