Differential sensitivity of C2-C12 striated muscle cells to lovastatin and pravastatin.
One of the major side-effects of the use of HMG CoA reductase inhibitors for the treatment of hypercholesterolemia is the development of myositis and, in some patients undergoing concomitant immunosuppressive treatment, the development of rhabdomyolysis. Experiments outlined in these studies demonstrate that inhibitors of HMG-CoA reductase activity which differ primary in the substitution of a methyl group for a hydroxyl group have differential effects on both cholesterol levels and cell viability in a striated muscle cell model, the mouse C2-C12 myoblast. Thus, concentrations as high as 200 microM of pravastatin had little effect on total cholesterol level while 25 microM of lovastatin decreased cellular cholesterol by over 90%. Simvastatin and lovastatin decreased viability of C2-C12 myoblasts by nearly 50% at concentrations as low as 1 and 5 microM, respectively, and decreased viability by almost 90% at 10 and 15 microM respectively. However, 300 microM of pravastatin decreased cell viability by less than 50%. The order of potency for the effects on cell viability wassimvastatin>lovastatin>>>pravastatin. The possible relationship between effects on cell viability and the development of myositis is discussed.
Gadbut
A P
AP
Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
Caruso
A P
AP
Galper
J B
JB
D000818:Animals; D000924:Anticholesteremic Agents / Q000737:chemistry / Q000633:toxicity*; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002784:Cholesterol / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008148:Lovastatin / Q000737:chemistry / Q000633:toxicity*; D051379:Mice; D015394:Molecular Structure; D009024:Morphogenesis / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D009220:Myositis / Q000139:chemically induced*; D017035:Pravastatin / Q000737:chemistry / Q000633:toxicity*; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D013329:Structure-Activity Relationship
D000924:Anticholesteremic Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D002784:Cholesterol; D008148:Lovastatin; D017035:Pravastatin