IN-VITRO MYOTOXICITY OF THE 3-HYDROXY-3-METHYLGLUTARYL COENZYME-A REDUCTASE INHIBITORS, PRAVASTATIN, LOVASTATIN, AND SIMVASTATIN, USING NEONATAL RAT SKELETAL MYOCYTES

Pravastatin, lovastatin, and simvastatin, drugs which lower cholestero l by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reduct ase, have been linked to skeletal myopathies in humans and rats. The m yotoxicity of these three drugs was compared, after 48 hr exposure, in cultures of primary neonatal rat skeletal myotubes. Measurements incl uded HMG CoA reductase activity ([C-14]acetate incorporation into chol esterol), indicators of membrane damage (CPK, LDH, and AST), cell viab ility (mitochondrial dehydrogenase metabolism of MTT), protein synthes is ([H-3]leucine incorporation), and energy status (ATP). All three dr ugs inhibited cholesterol synthesis to the same extent in rat hepatocy tes (IC50s approximately 0.07 mu M). Lovastatin- and simvastatin-induc ed inhibition of cholesterol synthesis in myotubes was unchanged compa red to that of hepatocytes, but pravastatin was 85-fold less potent (I C50 = 5.9 mu M) Protein synthesis and ATP levels were the most sensiti ve indicators of toxicity. Pravastatin (IC50 = 759 mu M) was > 100-fol d less inhibitory of protein synthesis than lovastatin (IC50 = 5.4 mu M) or simvastatin (IC50 = 1.9 mu M). Addition of mevalonic acid (the i mmediate product of the HMG CoA reductase reaction), as 100 mu M meval onic acid lactone, reversed the toxicity of all three drugs. Removal o f serum for 24-72 hr did not alter the toxicity of any of the drugs co mpared to cultures containing 10% serum, suggesting that differences i n protein binding did not account for the differences in toxicity of t he drugs. These results indicate that pravastatin is less myotoxic tha n lovastatin or simvastatin in this in vitro system using neonatal rat skeletal muscle cells, and this differential toxicity is correlated w ith the selective decrease in inhibition of HMG CoA reductase by prava statin in nonhepatic tissues. (C) 1995 Academic Press, Inc.