title: Efficacy of bezafibrate on fibroblasts of glutaric acidemia type II patients evaluated using an in vitro probe acylcarnitine assay.
abstract: BACKGROUND
  We evaluated the effects of bezafibrate (BEZ) on β-oxidation in fibroblasts obtained from patients with glutaric acidemia type II (GA2) of various clinical severities using an in vitro probe (IVP) assay.
  
  
  METHODS
  Cultured fibroblasts from 12 patients with GA2, including cases of the neonatal-onset type both with and without congenital anomalies (the prenatal- and neonatal-onset forms, respectively), the infantile-onset, and the myopathic forms, were studied. The IVP assay was performed by measuring acylcarnitines (ACs) in the cell culture medium of fibroblasts incubated with palmitic acid for 96h in the presence of 0-800μM BEZ using tandem mass spectrometry.
  
  
  RESULTS
  The IVP assay showed that 100μM BEZ markedly reduced the level of palmitoylcarnitine (C16) in the neonatal-onset, infantile-onset, and myopathic forms of GA2, either increasing or maintaining a high level of acetylcarnitine (C2), which serves as an index of energy production via β-oxidation. In the prenatal-onset form, although a small reduction of C16 was also observed in the presence of 100μM BEZ, the level of C2 remained low. At concentrations higher than 100μM, BEZ further decreased the level of ACs including C16, but a concentration over 400μM decreased the level of C2 in most cases.
  
  
  CONCLUSIONS
  BEZ at 100μM was effective for all GA2 phenotypes except for the prenatal-onset form, as a reduction of C16 without deterioration of C2 is considered to indicate improvement of β-oxidation. The effects of higher doses BEZ could not be estimated by the IVP assay but might be small or nonexistent.
authors: Department of Pediatrics, Shimane University, Faculty of Medicine, Izumo, Shimane, Japan. Electronic address: k-yamada@med.shimane-u.ac.jp.
authors: Kenji
authors: K
authors: Yamada
authors: Department of Pediatrics, Shimane University, Faculty of Medicine, Izumo, Shimane, Japan.
authors: Hironori
authors: H
authors: Kobayashi
authors: Department of Pediatrics, Shimane University, Faculty of Medicine, Izumo, Shimane, Japan; Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.
authors: Ryosuke
authors: R
authors: Bo
authors: Department of Pediatrics, Shimane University, Faculty of Medicine, Izumo, Shimane, Japan.
authors: Jamiyan
authors: J
authors: Purevsuren
authors: Department of Pediatrics, Shimane University, Faculty of Medicine, Izumo, Shimane, Japan.
authors: Yuichi
authors: Y
authors: Mushimoto
authors: Department of Pediatrics, Shimane University, Faculty of Medicine, Izumo, Shimane, Japan.
authors: Tomoo
authors: T
authors: Takahashi
authors: Department of Pediatrics, Shimane University, Faculty of Medicine, Izumo, Shimane, Japan.
authors: Yuki
authors: Y
authors: Hasegawa
authors: Department of Pediatrics, Shimane University, Faculty of Medicine, Izumo, Shimane, Japan.
authors: Takeshi
authors: T
authors: Taketani
authors: Department of Pediatrics, Shimane University, Faculty of Medicine, Izumo, Shimane, Japan.
authors: Seiji
authors: S
authors: Fukuda
authors: Department of Pediatrics, Shimane University, Faculty of Medicine, Izumo, Shimane, Japan.
authors: Seiji
authors: S
authors: Yamaguchi
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D001629:Bezafibrate / Q000494:pharmacology*; D002331:Carnitine / Q000031:analogs & derivatives* / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D020536:Enzyme Activators / Q000494:pharmacology; D005260:Female; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D057847:Lipid Regulating Agents / Q000494:pharmacology*; D008297:Male; D054069:Multiple Acyl Coenzyme A Dehydrogenase Deficiency / Q000188:drug therapy* / Q000378:metabolism; D010172:Palmitoylcarnitine / Q000378:metabolism; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists; D012867:Skin / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
chemical_list: D020536:Enzyme Activators; D057847:Lipid Regulating Agents; D047492:Peroxisome Proliferator-Activated Receptors; C116917:acylcarnitine; D010172:Palmitoylcarnitine; D002331:Carnitine; D001629:Bezafibrate
keywords: Bezafibrate; Fatty acid oxidation disorders; Glutaric acidemia type II; In vitro probe assay; Multiple acyl-CoA dehydrogenase deficiency