| The immunosuppressant drug FK506 prevents Fas-induced apoptosis in human hepatocytes. | |
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MedLine Citation:
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PMID: 15548389 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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FK506 is a potent immunosuppressive drug used for the prevention of graft rejection in organ transplantation. Experimental and clinical studies have shown correlations between apoptosis and graft rejection, and apoptosis also plays a role in cell death after ischemia-reperfusion injury in the rat liver. Fas-mediated apoptosis is very likely involved in allograft rejection and experimental evidence has shown a decrease of FasR expression in mouse hepatocytes produced by the drugs. On the basis of these findings we have investigated the protective effect of FK506 in comparison with cyclosporine A (CsA) on Fas-induced apoptosis, by analysing the activation of downstream effector caspases in human hepatocytes. Apoptosis was induced by treatment with agonistic antibodies against FasR, which resulted in a significant activation of caspase-3 after 12 h. Prevention of the downstream activation of the caspase cascade and apoptosis was observed when hepatocytes were pre-treated for 3 h with immunosuppressant drugs. A significant reduction (ca. 30-40%) of caspase-3 activation by 5 microM FK506 and CsA was observed. Along with less activation of caspase-3 a decrease of apoptotic DNA fragmentation was found. In addition, FK506 significantly reduced not only caspase-8 but also caspase-9 activation, to a similar extent as CsA, thus suggesting a protective effect at the mitochondrial level of this drug, as has already been reported for CsA. These effects of FK506 help to explain its strong anti-rejection properties and suggest promising benefits of pharmacological preconditioning on ischemia-reperfusion injury following liver transplantation. |
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Authors:
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M J Gómez-Lechón; A Serralta; M T Donato; N Jiménez; E O'connor; J V Castell; J Mir |
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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: Biochemical pharmacology Volume: 68 ISSN: 0006-2952 ISO Abbreviation: Biochem. Pharmacol. Publication Date: 2004 Dec |
Date Detail:
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Created Date: 2004-11-19 Completed Date: 2005-03-24 Revised Date: 2006-11-15 |
Medline Journal Info:
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Nlm Unique ID: 0101032 Medline TA: Biochem Pharmacol Country: England |
Other Details:
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Languages: eng Pagination: 2427-33 Citation Subset: IM |
Affiliation:
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Centro de Investigación, Unidad de Hepatología Experimental, Hospital Universitario La Fe, Avda Campanar 21, E-47009 Valencia, Spain. gomez_mjo@gva.es |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Adult Aged Antigens, CD95 / pharmacology* Apoptosis* Caspase 3 Caspase 8 Caspases / metabolism DNA Fragmentation / drug effects Drug Interactions Enzyme Activation / drug effects Female Hepatocytes / cytology, drug effects*, enzymology Humans Immunosuppressive Agents / pharmacology* Male Middle Aged Tacrolimus / pharmacology* |
| Chemical | |
Reg. No./Substance:
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0/Antigens, CD95; 0/Immunosuppressive Agents; 109581-93-3/Tacrolimus; EC 3.4.22.-/CASP3 protein, human; EC 3.4.22.-/CASP8 protein, human; EC 3.4.22.-/Casp3 protein, mouse; EC 3.4.22.-/Casp3 protein, rat; EC 3.4.22.-/Casp8 protein, mouse; EC 3.4.22.-/Casp8 protein, rat; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspase 8; EC 3.4.22.-/Caspases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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