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1069283 
Journal Article 
Multi-Tissue Characterization Of Rhabdomyolysis For The High Profile Failure Cerivastatin 
Ganter, B; Kolaja, KL 
2005 
Toxicological Sciences
ISSN: 1096-6080
EISSN: 1096-0929 
84 
1-S 
105 
Gene-expression-based chemogenomic analysis of cerivastatin discriminated it from other HMG-CoA reductase inhibitors (i.e. statins). The ability to identify cerivastatin as distinct from other statins is critical since this compound was withdrawn from the market due to rhabdomyolysis and lethality. We have profiled 7 statins (lovastatin, simvastatin, cerivastatin, mevastatin, fluvastatin, atorvastatin and pravastatin) and close to 600 other compounds (3, 700 different dose-time treatments) in short, repeat dose studies in rats. In liver, kidney, and muscle, cerivastatin was differentiated based on its ability to perturb genes associated with hepatotoxicity, inflammatory response, and cytoskeleton. An in-depth analysis of genes perturbed, shows cerivastatin is the most potent inducer of inflammation in kidney and muscle among all compounds studied. Hierarchical clustering of liver expression data using genes correlated to ALT and AST revealed that cerivastatin clustered with a number of classic liver toxicants including methapyrilene, chloroform and 1-napthylisothiocyanate. Perturbations in hepatic gene expression predict ammonia-induced toxicity due to repression of the urea cycle, possibly leading to secondary muscle fatigue or muscle damage, and a dysregulation of cytoskeleton genes. The dysregulation of cytoskeleton genes observed in liver is further exacerbated in muscle by the fact that key ECM and connective tissue proteins, including tenascin C, fibronectin, laminin, and collagen, are downregulated. The cytoskeleton dysregulation observed in muscle, combined with a gene expression pattern suggesting an altered excitation-contraction coupling due to an altered Ca(2+) buffering capacity, may explain the mechanism of myocyte necrosis that precedes rhabdomyolysis. To conclude, liver gene expression data in short-term rat studies discriminated cerivastatin from its peers and shed light on its risk of toxicity, while the muscle expression data confirmed the mechanistic information relevant to target organ toxicity 
adverse effects; Alanine Transaminase; analysis; Animals; Aspartate Aminotransferases; chemically induced; Chloroform; Collagen; Connective Tissue; drug effects; enzymology; Extracellular Matrix Proteins; Gene Expression; Genes; genetics; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Inhibitors; Kidney; Light; Liver; metabolism; Methapyrilene; Muscles; Necrosis; Proteins; Pyridines; Rats; Rhabdomyolysis; Risk; secondary; toxicity; Toxicology; TOXLINE 2000-03/19/2007; Urea