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
Dm. Peffley et al., 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, Biochemical pharmacology, 56(4), 1998, pp. 439-449
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.