title: Statin-induced Ca(2+) release was increased in B lymphocytes in patients who showed elevated serum creatine kinase during statin treatment.
abstract: OBJECTIVE
  Statins are effective in lowering cholesterol levels, but cause fatal rhabdomyolysis in susceptible individuals. Because it has been hypothesized that muscle damage could result from alterations in Ca(2+) homeostasis in muscle cells, we tested whether measuring statin-induced changes in intracellular calcium ([Ca(2+)](i)) is useful for predicting susceptibility to statin-muscle damage, using human CD19+ primary B lymphocytes.
  
  
  METHODS
  Statin-induced alterations in [Ca(2+)](i) were studied using the human THP-1 cell line and CD19+ primary B lymphocytes. Changes in [Ca(2+)](i) were measured directly in fluo-3- loaded cells using either single or dual-color flow cytometry.
  
  
  RESULTS
  The Ca(2+) release study suggested that statin-induced changes in [Ca(2+)](i) were due to Ca(2+) release from ryanodine-sensitive Ca(2+) stores and mitochondrial compartments. Further, statin users who experienced elevated creatine kinase (n=8) exhibited significantly greater statin-induced Ca(2+) release in B cells than healthy volunteers (n=45) and statin users without elevated creatine kinase (n=16), while no difference was seen between the latter two groups.
  
  
  CONCLUSIONS
  Statin-induced Ca(2+) release from ryanodine-sensitive stores and mitochondria may contribute to myotoxicity. The laboratory test for Ca(2+) release using CD19+ primary B lymphocytes may be useful to predict susceptibility to statin-induced muscle toxicity prior to statin use.
authors.affiliation: Department of Informative Clinical Medicine, Gifu University Graduate School of Medicine, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Hattori
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Saito
authors.forename: Masao
authors.initials: M
authors.lastname: Takemura
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Ito
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Ohta
authors.forename: Hisayasu
authors.initials: H
authors.lastname: Wada
authors.forename: Yoshitatsu
authors.initials: Y
authors.lastname: Sei
authors.forename: Mitsunobu
authors.initials: M
authors.lastname: Kawamura
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Seishima
mesh_terms: D000328:Adult; D000368:Aged; D018941:Antigens, CD19 / Q000096:biosynthesis; D001402:B-Lymphocytes / Q000187:drug effects* / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D003402:Creatine Kinase / Q000097:blood* / Q000378:metabolism; D005434:Flow Cytometry / Q000379:methods; D005456:Fluorescent Dyes / Q000494:pharmacology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism
chemical_list: D018941:Antigens, CD19; D005456:Fluorescent Dyes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019837:Ryanodine Receptor Calcium Release Channel; D003402:Creatine Kinase; D002118:Calcium