Cholesterol biosynthesis regulation and protein changes in rat liver following treatment with fluvastatin

The enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase is a k ey regulator in cholesterol biosynthesis and HMG CoA reductase inhibitors ( statins) have become a widely prescribed family of lipid lowering agents. C holesterol synthesis occurs predominantly in liver which is the target orga n of statins. We studied the effects of fluvastatin (Lescol((R))), a member of the statin family, on hepatic protein regulation. Male F344 rats treate d with 0.8 mg/kg per day fluvastatin or 24 mg/kg per day fluvastatin for 7 days showed treatment-related changes in 58 liver proteins (P < 0.005). Maj or effects were evident in the cholesterol biosynthesis pathway including t he induction of enzymes upstream and downstream of the target enzyme HMG Co A reductase. Treatment also triggered alterations in key enzymes of carbohy drate metabolism and was associated with changes in a heterogeneous set of cellular stress proteins involved in cytoskeletal structure, calcium homeos tasis and protease activity. The latter set of protein alterations indicate s that hepatotoxicity is associated with high-dose treatment. Based on the results it is suggested that HMG-CoA synthase and isopentenyl-diphosphate d elta-isomerase may be explored as alternative drug targets and that the ind uction levels of these enzymes may serve as a measure of potency of individ ual statin drugs. It is proposed that efficacy and cellular stress markers discovered in this study may be used in a high throughput screen (HTS) assa y format to compare efficiently and accurately the therapeutic windows of d ifferent members of the statin family. (C) 2001 Elsevier Science Ireland Lt d. All rights reserved.