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 10 microM) induced a dose-dependent reduction of DNA synthesis, assessed by 3H-thymidine incorporation in rat hepatocytes, which dropped by approximately 60% at a drug concentration of 10 microM. 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 apoptotic 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.
Satoh
T
T
Third Department of Internal Medicine, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
Isobe
H
H
Ayukawa
K
K
Sakai
H
H
Nawata
H
H
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects*; D002478:Cells, Cultured; D008078:Cholesterol, LDL / Q000494:pharmacology; D002843:Chromatin / Q000648:ultrastructure; D004247:DNA / Q000096:biosynthesis*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005204:Farnesol / Q000494:pharmacology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007541:Isopentenyladenosine; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D008798:Mevalonic Acid / Q000378:metabolism / Q000494:pharmacology; D017035:Pravastatin / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
D008078:Cholesterol, LDL; D002843:Chromatin; D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C001478:N(6)-(delta(2)-isopentenyl)adenine; D005204:Farnesol; D004815:Epidermal Growth Factor; D007541:Isopentenyladenosine; D004247:DNA; D000225:Adenine; D017035:Pravastatin; D008798:Mevalonic Acid