Document Detail


The immunosuppressant drug FK506 prevents Fas-induced apoptosis in human hepatocytes.
MedLine Citation:
PMID:  15548389     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
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:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Biochemical pharmacology     Volume:  68     ISSN:  0006-2952     ISO Abbreviation:  Biochem. Pharmacol.     Publication Date:  2004 Dec 
Date Detail:
Created Date:  2004-11-19     Completed Date:  2005-03-24     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0101032     Medline TA:  Biochem Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  2427-33     Citation Subset:  IM    
Affiliation:
Centro de Investigación, Unidad de Hepatología Experimental, Hospital Universitario La Fe, Avda Campanar 21, E-47009 Valencia, Spain. gomez_mjo@gva.es
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MeSH Terms
Descriptor/Qualifier:
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:
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

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