Fibrates and statins rapidly and synergistically induce pyruvate dehydrogenase kinase 4 mRNA in the liver and muscles of mice.
We previously identified pyruvate dehydrogenase kinase 4 (PDK4) mRNA as a most rapidly induced mRNA by fibrates and suggested the possibility that the coupled induction of PDK4 and reduction of serum triglyceride and fatty acid levels can cause protein degradation in muscles. To investigate whether the drugs that are known to have a risk of rhabdomyolysis induce PDK4 mRNA in skeletal muscle, the effects of statins and new quinolon anti-bacterial drugs on the expression levels of the mRNA were examined using mice and cultured cells. Several statins and new quinolon anti-bacterial drugs solely induced PDK4 mRNA in the muscle as efficiently as fibrates and at least some combinations were synergistic. The present results suggest that induction of PDK4 mRNA is involved in the drug induced acute rhabdomyolysis when the muscle is restricted to use fatty acids as a major energy source.
Motojima
Kiyoto
K
Department of Biochemistry, Meiji Pharmaceutical University, Kiyose, Tokyo, Japan. motojima@my-pharm.ac.jp
Seto
Kouichi
K
D000818:Animals; D001629:Bezafibrate / Q000494:pharmacology*; D002478:Cells, Cultured; D004357:Drug Synergism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007527:Isoenzymes / Q000096:biosynthesis* / Q000235:genetics; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009132:Muscles / Q000187:drug effects* / Q000201:enzymology; D011494:Protein Kinases / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007527:Isoenzymes; D012333:RNA, Messenger; D011494:Protein Kinases; C403287:pyruvate dehydrogenase kinase 4; D001629:Bezafibrate