Preventive effects of bicarbonate on cerivastatin-induced apoptosis.
Although HMG-CoA reductase inhibitors such as statins are the most widely used cholesterol-lowering agents, there is a risk of myopathy or rhabdmyolysis occurring in patients taking these drugs. It has been reported that a number of lipophilic statins cause apoptosis in various cells, but it is still not clear whether intracellular acidification is involved in statin-induced apoptosis. There have been few studies aimed at identifying compounds that suppress statin-induced myotoxicity. In the present study, we examined the relationship between cerivastatin-induced apoptosis and intracellular acidification and the effect of bicarbonate on cerivastatin-induced apoptosis using an RD cell line as a model of in vitro skeletal muscle. Cerivastatin reduced the number of viable cells and caused dramatic morphological changes and DNA fragmentation in a concentration-dependent manner. Moreover, cerivastatin-induced apoptosis was associated with intracellular acidification and caspase-9 and -3/7 activation. On the other hand, bicarbonate suppressed cerivastatin-induced pH alteration, caspase activation, morphological change and reduction of cell viability. Accordingly, bicarbonate suppressed statin-induced apoptosis. The strategy to combine statins with bicarbonate can lead to reduction in the chance of the severe adverse events including myopathy or rhabdmyolysis.
Kobayashi
Masaki
M
Department of Clinical Pharmaceutics & Therapeutics, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12-jo, Nishi-6-chome, Kita-ku, Sapporo 060-0812, Japan.
Kaido
Fumie
F
Kagawa
Toshiki
T
Itagaki
Shirou
S
Hirano
Takeshi
T
Iseki
Ken
K
D017209:Apoptosis / Q000187:drug effects*; D001692:Biological Transport; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D048430:Cell Shape / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005464:Fluorobenzenes / Q000378:metabolism / Q000633:toxicity*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000378:metabolism / Q000633:toxicity*; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020011:Protective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D011725:Pyridines / Q000378:metabolism / Q000633:toxicity*; D011743:Pyrimidines / Q000378:metabolism / Q000633:toxicity*; D012206:Rhabdomyolysis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D018233:Rhabdomyosarcoma, Embryonal / Q000378:metabolism / Q000473:pathology; D000068718:Rosuvastatin Calcium; D017693:Sodium Bicarbonate / Q000494:pharmacology* / Q000627:therapeutic use; D013449:Sulfonamides / Q000378:metabolism / Q000633:toxicity*
D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D020011:Protective Agents; D011725:Pyridines; D011743:Pyrimidines; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium; D017693:Sodium Bicarbonate; C086276:cerivastatin; C506433:CASP9 protein, human; D053148:Caspase 3; D053179:Caspase 7; D053453:Caspase 9