| A novel role for ursodeoxycholic acid in inhibiting apoptosis by modulating mitochondrial membrane perturbation. | |
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MedLine Citation:
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PMID: 9637713 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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C M Rodrigues; G Fan; X Ma; B T Kren; C J Steer |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: The Journal of clinical investigation Volume: 101 ISSN: 0021-9738 ISO Abbreviation: J. Clin. Invest. Publication Date: 1998 Jun |
Date Detail:
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Created Date: 1998-07-14 Completed Date: 1998-07-14 Revised Date: 2009-11-18 |
Medline Journal Info:
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Nlm Unique ID: 7802877 Medline TA: J Clin Invest Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 2790-9 Citation Subset: AIM; IM |
Affiliation:
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Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota 55455, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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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:
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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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