Document Detail


In vitro investigations on the differential pro-oxidant and/or antioxidant properties of cyclosporin A and tacrolimus in human and rat liver microsomes.
MedLine Citation:
PMID:  16724577     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECTIVE: The use of cyclosporin A (CSA) and tacrolimus (TAC) in organ transplantation and in the therapy of immune disorders is often hampered by adverse effects, mainly nephro-, hepato- and neurotoxicity. For the development of these side effects, among others, an increased formation of reactive oxygen species, probably generated by the cytochrome P450 (CYP) system, has been accused. Since in this respect literature data are inconsistent, in the present study possible pro- and/or antioxidant effects of CSA and TAC and the involvement of the CYP system were re-evaluated in vitro. METHODS: Effects of CSA and TAC were examined on CYP mediated oxidase functions by stimulated lipid peroxidation (LPO), H2O2 production, and lucigenin (LC) or luminol (LM) amplified chemiluminescence (CL) in liver microsomes of either untreated rats or of rats treated with beta-naphthoflavone (BNF), phenobarbital (PB) or dexamethasone (DEX) and in human liver microsomes. RESULTS: In rat liver microsomes, CSA displayed pro-oxidant properties (though only very slightly), whereas in human liver microsomes small antioxidant effects were seen. With TAC in both species the antioxidant capacity prevailed. Treatment of rats with BNF or DEX caused an increase in the pro-oxidant effects of CSA with respect to LPO or LM-CL, whereas in liver microsomes of DEX-treated rats H2O2 production and LC-CL were diminished. CONCLUSIONS: CSA seems to have both pro-oxidant and antioxidant properties, whereas with TAC mainly an antioxidant capacity was seen. The CYP system seems to be involved in the pro-oxidant influence of CSA. Whether pro-oxidant or antioxidant effects predominate may depend on the antioxidant capacity of a tissue and on the CYP isoforms mainly present.
Authors:
A Lupp; U D Kuhn; E Karge; G Adam; C Fleck
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Publication Detail:
Type:  In Vitro; Journal Article    
Journal Detail:
Title:  International journal of clinical pharmacology and therapeutics     Volume:  44     ISSN:  0946-1965     ISO Abbreviation:  Int J Clin Pharmacol Ther     Publication Date:  2006 May 
Date Detail:
Created Date:  2006-05-26     Completed Date:  2007-07-20     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9423309     Medline TA:  Int J Clin Pharmacol Ther     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  225-32     Citation Subset:  IM    
Affiliation:
Institute of Pharmacology and Toxicology, Friedrich Schiller University, 07740 Jena, Germany. Amelie.Lupp@mti.uni-jena.de
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MeSH Terms
Descriptor/Qualifier:
Animals
Antioxidants / pharmacology*
Cyclosporine / pharmacology*
Cytochrome P-450 Enzyme System / biosynthesis*
Dexamethasone / pharmacology
Dose-Response Relationship, Drug
Enzyme Induction
Humans
Hydrogen Peroxide / metabolism
Immunosuppressive Agents / pharmacology*
Isoenzymes / biosynthesis
Lipid Peroxidation
Liver / drug effects*,  enzymology
Male
Microsomes, Liver
Oxidants / pharmacology*
Phenobarbital / pharmacology
Rats
Rats, Wistar
Tacrolimus / pharmacology*
beta-Naphthoflavone / pharmacology
Chemical
Reg. No./Substance:
0/Antioxidants; 0/Immunosuppressive Agents; 0/Isoenzymes; 0/Oxidants; 109581-93-3/Tacrolimus; 50-02-2/Dexamethasone; 50-06-6/Phenobarbital; 59865-13-3/Cyclosporine; 6051-87-2/beta-Naphthoflavone; 7722-84-1/Hydrogen Peroxide; 9035-51-2/Cytochrome P-450 Enzyme System

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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