Document Detail


Adverse effect of fenofibrate on branched-chain alpha-ketoacid dehydrogenase complex in rat's liver.
MedLine Citation:
PMID:  19819289     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Branched-chain alpha-ketoacid dehydrogense complex (BCKDH) is a regulatory enzyme of valine, isoleucine and leucine catabolism. Its activity is mainly regulated by covalent modification achieved by a specific BCKDH kinase (BDK) and phosphatase (BDP). The goal of our study was to investigate the effect of increasing doses of fenofibrate on BDK and BCKDH activities in rat's liver. For 14 days fenofibrate was administrated to Wistar male rats (fed chow containing 8% protein) at one of the daily doses: 5, 10, 20 and 50mg/kg. Control group was given only vehicle (0.3% methylcellulose). BDK activity as well as actual BCKDH activity and total BCKDH activity were assayed spectrophotometrically and BDK protein amount was determined by Western blotting. In rats administered fenofibrate BDK activity decreased by 61%, 64%, 66% and 89% (p<0.0001). Changes in BDK protein expression did not correspond with changes in BDK activity. BCKDH complex actual activity was 3.7+/-0.3, 4.1+/-0.1, 4.6+/-0.3 and 4.0+/-0.3fold higher (p<0.0001) and BCKDH total activity 1.3+/-0.1, 1.3+/-0.1, 1.5+/-0.1 and 1.3+/-0.1fold higher comparing to control group (p<0.001). BCKDH activity state (percentage of active, dephosphorylated form) increased 2.8+/-0.2, 3.1+/-0.1, 3.2+/-0.1 and 3.0+/-0.1fold (p<0.0001). In addition, fenofibrate prevented body weight gain starting from the dose of 10mg/kg/day and induced hepatomegaly in a dose-dependent manner. It can be concluded that fenofibrate under condition of protein restriction starting from the lowest dose inhibits BDK activity at the posttranslational level and increases BCKDH activity state. It is conceivable that fenofibrate decreases of branched-chain amino acids (BCAA) levels by stimulation of their catabolism. Since leucine plays an important role in up-regulation of protein anabolism in muscles, the reduced level of this amino acid may be one of the factors involved in pathomechanism of myopathy observed during treatment with fenofibrate.
Authors:
Malgorzata Knapik-Czajka; Anna Gozdzialska; Jerzy Jaskiewicz
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-10-09
Journal Detail:
Title:  Toxicology     Volume:  266     ISSN:  1879-3185     ISO Abbreviation:  Toxicology     Publication Date:  2009 Dec 
Date Detail:
Created Date:  2009-11-25     Completed Date:  2009-12-11     Revised Date:  2012-06-06    
Medline Journal Info:
Nlm Unique ID:  0361055     Medline TA:  Toxicology     Country:  Ireland    
Other Details:
Languages:  eng     Pagination:  1-5     Citation Subset:  IM    
Affiliation:
Jagiellonian University Medical College, Faculty of Pharmacy, Department of Analytical Biochemistry, Medyczna 9 St., 30-688 Krakow, Poland. mfknapik@cyf-kr.edu.pl
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MeSH Terms
Descriptor/Qualifier:
3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide) / metabolism*
Amino Acids, Branched-Chain / metabolism*
Animals
Blotting, Western
Body Weight / drug effects
Diet, Protein-Restricted
Dose-Response Relationship, Drug
Eating / drug effects
Enzyme Activation
Fenofibrate / toxicity*
Hepatomegaly / chemically induced
Hypolipidemic Agents / toxicity*
Liver / drug effects*,  enzymology,  pathology
Male
Multienzyme Complexes
Organ Size / drug effects
Phosphorylation
Protein Kinases / metabolism
Rats
Rats, Wistar
Spectrophotometry
Chemical
Reg. No./Substance:
0/Amino Acids, Branched-Chain; 0/Hypolipidemic Agents; 0/Multienzyme Complexes; 49562-28-9/Fenofibrate; EC 1.2.4.4/3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide); EC 2.7.-/Protein Kinases; EC 2.7.11.4/(3-methyl-2-oxobutanoate dehydrogenase (lipoamide)) kinase

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


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