The novel cholesterol-lowering drug SR-12813 inhibits cholesterol synthesis via an increased degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase

SR-12813 (tetra-ethyl 2-(3,5-di-tert-butyl-4-hydroxy-phenyl)ethenyl-1,1- bisphosphonate) lowers plasma cholesterol in five species. In this paper we investigate the underlying mechanism using Hep G2 cells. SB-12813 inhibited incorporation of tritiated water into cholesterol with an IC₅₀ of 1.2 μM but had no effect on fatty acid synthesis. Furthermore, SR-12813 reduced cellular 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity with an IC₅₀ of 0.85 μM. The inhibition of HMG-CoA reductase activity was rapid with a T( 1/2 ) of 10 min. After a 16-h incubation with SR-12813, mRNA levels of HMG-CoA reductase and low density lipoprotein (LDL) receptor were increased. The increased expression of LDL receptor translated into a higher LDL uptake, which can explain the primary hypocholesterolemic effect of SR- 12813 in vivo. Western blot analysis indicated that the amount of HMG-CoA reductase protein rapidly decreased in the presence of SR-12813. Pulse-chase experiments with [³⁵S]methionine showed that the T( 1/2 ) of HMG-CoA reductase degradation decreased in the presence of SR-12813 from 90 to 20 min. Pre- incubation with 50 μM of lovastatin did not prevent the effects of SR-12813 on HMG-CoA reductase degradation, indicating that the compound does not need mevalonate-derived regulators for its action. It is concluded that SR-12813 inhibits cholesterol synthesis mainly by an enhanced degradation of HMG-CoA reductase.