The effects of pravastatin, an HMG-CoA reductase inhibitor, on cell viability and dna production of rat hepatocytes

Some metabolites and products of mevalonic acid are involved in various cellular functions, particularly cell growth. In this study, we assessed the effects of pravastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, on cell viability and DNA production of rat hepatocytes stimulated with epidermal growth factor. Pravastatin (0.1 to 10μM) induced a dose-dependent reduction of DNA synthesis, assessed by 3H-thymidine incorporation in rat hepatocytes, which dropped by approximately 60% al a drug concentration of 10 μM. This suppression of DNA synthesis was nearly reversed by exogenous mevalonic acid, but was not prevented by purified low-density lipoprotein cholesterol. Pravastatin did not affect the mitochondrial reduction of Dimethylthiazolyl-diphenyl-tetrazolium bromide (MTT), but induced apoptotic change as assessed by nuclear chromatin staining. This apoptolic change was also reversed by exogenous mevalonic acid. These results indicate that mevalonic acid metabolites are necessary for DNA synthesis by rat hepatocytes stimulated by epidermal growth factor and for suppressing cell death.