Document Detail


A novel role for ursodeoxycholic acid in inhibiting apoptosis by modulating mitochondrial membrane perturbation.
MedLine Citation:
PMID:  9637713     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The hydrophilic bile salt ursodeoxycholic acid (UDCA) protects against the membrane-damaging effects associated with hydrophobic bile acids. This study was undertaken to (a) determine if UDCA inhibits apoptosis from deoxycholic acid (DCA), as well as from ethanol, TGF-beta1, Fas ligand, and okadaic acid; and to (b) determine whether mitochondrial membrane perturbation is modulated by UDCA. DCA induced significant hepatocyte apoptosis in vivo and in isolated hepatocytes determined by terminal transferase-mediated dUTP-digoxigenin nick end-labeling assay and nuclear staining, respectively (P < 0.001). Apoptosis in isolated rat hepatocytes increased 12-fold after incubation with 0.5% ethanol (P < 0.001). HuH-7 cells exhibited increased apoptosis with 1 nM TGF-beta1 (P < 0. 001) or DCA at >/= 100 microM (P < 0.001), as did Hep G2 cells after incubation with anti-Fas antibody (P < 0.001). Finally, incubation with okadaic acid induced significant apoptosis in HuH-7, Saos-2, Cos-7, and HeLa cells. Coadministration of UDCA with each of the apoptosis-inducing agents was associated with a 50-100% inhibition of apoptotic changes (P < 0.001) in all the cell types. Also, UDCA reduced the mitochondrial membrane permeability transition (MPT) in isolated mitochondria associated with both DCA and phenylarsine oxide by > 40 and 50%, respectively (P < 0.001). FACS(R) analysis revealed that the apoptosis-inducing agents decreased the mitochondrial transmembrane potential and increased reactive oxygen species production (P < 0.05). Coadministration of UDCA was associated with significant prevention of mitochondrial membrane alterations in all cell types. The results suggest that UDCA plays a central role in modulating the apoptotic threshold in both hepatocytes and nonliver cells, and inhibition of MPT is at least one pathway by which UDCA protects against apoptosis.
Authors:
C M Rodrigues; G Fan; X Ma; B T Kren; C J Steer
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  101     ISSN:  0021-9738     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  1998 Jun 
Date Detail:
Created Date:  1998-07-14     Completed Date:  1998-07-14     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  2790-9     Citation Subset:  AIM; IM    
Affiliation:
Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota 55455, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Apoptosis / drug effects*
Cell Membrane / drug effects
Cholagogues and Choleretics / pharmacology*
Deoxycholic Acid / toxicity
Ethanol / toxicity
Fas Ligand Protein
Liver / drug effects,  pathology*,  ultrastructure
Male
Membrane Glycoproteins / toxicity
Mitochondria, Liver / drug effects,  ultrastructure*
Rats
Rats, Sprague-Dawley
Transforming Growth Factor beta / toxicity
Ursodeoxycholic Acid / pharmacology*
Chemical
Reg. No./Substance:
0/Cholagogues and Choleretics; 0/Fas Ligand Protein; 0/Membrane Glycoproteins; 0/Tnfsf6 protein, rat; 0/Transforming Growth Factor beta; 128-13-2/Ursodeoxycholic Acid; 64-17-5/Ethanol; 83-44-3/Deoxycholic Acid
Comments/Corrections

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