Adverse effect of fenofibrate on branched-chain alpha-ketoacid dehydrogenase complex in rat's liver.
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.
Knapik-Czajka
Malgorzata
M
Jagiellonian University Medical College, Faculty of Pharmacy, Department of Analytical Biochemistry, Medyczna 9 St., 30-688 Krakow, Poland. mfknapik@cyf-kr.edu.pl
Gozdzialska
Anna
A
Jaskiewicz
Jerzy
J
D042942:3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide) / Q000378:metabolism*; D000597:Amino Acids, Branched-Chain / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D018753:Diet, Protein-Restricted; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D004789:Enzyme Activation; D011345:Fenofibrate / Q000633:toxicity*; D006529:Hepatomegaly / Q000139:chemically induced; D000960:Hypolipidemic Agents / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008297:Male; D009097:Multienzyme Complexes; D009929:Organ Size / Q000187:drug effects; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013053:Spectrophotometry
D000597:Amino Acids, Branched-Chain; D000960:Hypolipidemic Agents; D009097:Multienzyme Complexes; D042942:3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide); D011494:Protein Kinases; C035627:(3-methyl-2-oxobutanoate dehydrogenase (lipoamide)) kinase; D011345:Fenofibrate