DOWN-REGULATION OF 3-HYDROXY-3-METHYLGLUTARYL COENZYME-A REDUCTASE MESSENGER-RNA LEVELS AND SYNTHESIS IN SYRIAN-HAMSTER C100 CELLS BY THE OXIDOSQUALENE CYCLASE INHIBITOR YLOXY)-2'-FLUORO-PHENYL]-(4-BROMOPHENYL)-METHANONE (RO-48-8071) - COMPARISON TO SIMVASTATIN

In vivo inhibition of 2,3-oxidosqualene:lanosterol cyclase (OSC, E.C. 5.4.99.7)-the enzyme which catalyzes the cyclization of monooxidosqual ene to lanosterol-does not result in elevated 3-hydroxy-3-methylglutar yl CoA reductase (HMGR) activity. This trait is attributed to increase d levels of oxysterols, produced upon partial inhibition of OSC, that suppress HMGR and other sterol-responsive genes. The OSC inhibitor ylo xy)-2'-fluoro-phenyl]-(4-bromophenyl)-methanone (Ro 48-8071) was shown earlier to lower low-density lipoprotein (LDL) cholesterol in hamster s with no increase in hepatic HMGR, in contrast to simvastatin. To del ineate the regulatory mechanism(s) by which Ro 48-8071 reduces cholest erol synthesis without raising HMGR levels, Syrian hamster C100 cells were incubated with either Po 48-8071 or simvastatin, and their effect s on cholesterol synthesis and LDL uptake, as well as on HMGR mRNA lev els and rates of synthesis, were determined. Using RNase protection an d radioimmunoprecipitation assays, we found that, in the absence of LD L in the culture medium, both HMGR mRNA levels and synthesis were redu ced with concentrations of Ro 48-8071 inhibiting cholesterol synthesis by 50-75%, whereas LDL uptake was either reduced or unchanged. In con trast, simvastatin, at concentrations inhibiting cholesterol synthesis by the same 50-75%, increased both HMGR mRNA levels and synthesis, as well as LDL uptake. In the presence of LDL, HMGR mRNA levels and synt hesis along with LDL uptake were Little affected after incubation with Po 48-8071. Still, simvastatin markedly increased both HMGR mRNA leve ls and synthesis in cells incubated in the presence of LDL, leaving LD L uptake unaffected. These data suggest that inhibition of OSC by Ro 4 8-8071 results in an indirect down-regulation of HMGR mRNA levels and synthesis. BIOCHEM PHARMACOL 56;4: 439-449, 1998. (C) 1998 Elsevier Sc ience Inc.