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2,3-Oxidosqualene:lanosterol cyclase (OSC, E.C. 5.4.99.7) represents a unique
target for a cholesterol lowering drug. Partial inhibition of OSC should reduce
synthesis of lanosterol and subsequent sterols, and also stimulate the
production of epoxysterols that repress HMG-CoA reductase expression, generating
a synergistic, self-limited negative regulatory loop. Hence, the pharmacological
properties of Ro 48-8.071, a new OSC inhibitor, were compared to that of an
HMG-CoA reductase inhibitor, simvastatin. Ro 48-8.071 blocked human liver OSC
and cholesterol synthesis in HepG2 cells in the nanomolar range; in cells it
triggered the production of monooxidosqualene, dioxidosqualene, and
epoxycholesterol. It was safe in hamsters, squirrel monkeys and Göttingen
minipigs at pharmacologically active doses, lowering LDL approximately 60% in
hamsters, and at least 30% in the two other species, being at least as
efficacious as safe doses of simvastatin. The latter was hepatotoxic in hamsters
at doses > 30 mumol/kg/day limiting its window of efficacy. Hepatic
monooxidosqualene increased dose-dependently after treatment with Ro 48-8.071,
up to approximately 20 micrograms/g wet liver or less than 1% of hepatic
cholesterol, and it was inversely correlated with LDL levels. Ro 48-8.071 did
not reduce coenzyme Q10 levels in liver and heart of hamsters, and importantly
did not trigger an overexpression of hepatic HMG-CoA reductase, squalene
synthase, and OSC itself. In strong contrast, simvastatin stimulated these
enzymes dramatically, and reduced coenzyme Q10 levels in liver and heart.
Altogether these findings clearly differentiate the OSC inhibitor Ro 48-8.071
from simvastatin, and support the view that OSC is a distinct key component in
the regulation of the cholesterol synthesis pathway.
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