Preventive effects of bicarbonate on cerivastatin-induced apoptosis.

Abstract

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.

• Authors: Masaki Kobayashi, Fumie Kaido, Toshiki Kagawa, Shirou Itagaki, Takeshi Hirano, Ken Iseki
• Journal: International journal of pharmaceutics (Int J Pharm) Vol. 341 Issue 1-2 Pg. 181-8 (Aug 16 2007) ISSN: 0378-5173 [Print] Netherlands
• PMID: 17553641 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Fluorobenzenes
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• Protective Agents
• Pyridines
• Pyrimidines
• Sulfonamides
• Rosuvastatin Calcium
• Sodium Bicarbonate
• cerivastatin
• CASP9 protein, human
• Caspase 3
• Caspase 7
• Caspase 9

Topics

• Apoptosis (drug effects)
• Biological Transport
• Caspase 3 (metabolism)
• Caspase 7 (metabolism)
• Caspase 9 (metabolism)
• Cell Line, Tumor
• Cell Shape (drug effects)
• Cell Survival (drug effects)
• DNA Fragmentation (drug effects)
• Dose-Response Relationship, Drug
• Enzyme Activation
• Fluorobenzenes (metabolism, toxicity)
• Humans
• Hydrogen-Ion Concentration
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (metabolism, toxicity)
• Muscle, Skeletal (drug effects, metabolism, pathology)
• Protective Agents (pharmacology, therapeutic use)
• Pyridines (metabolism, toxicity)
• Pyrimidines (metabolism, toxicity)
• Rhabdomyolysis (chemically induced, metabolism, pathology, prevention & control)
• Rhabdomyosarcoma, Embryonal (metabolism, pathology)
• Rosuvastatin Calcium
• Sodium Bicarbonate (pharmacology, therapeutic use)
• Sulfonamides (metabolism, toxicity)