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Volume 271, Number 24, Issue of June 14, 1996 pp. 14376-14382
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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The Novel Cholesterol-lowering Drug SR-12813 Inhibits Cholesterol Synthesis via an Increased Degradation of 3-Hydroxy-3-methylglutaryl-coenzyme A Reductase

(Received for publication, February 12, 1996, and in revised form, March 22, 1996)

Theo A. Berkhout , Helen M. Simon , Dilip D. Patel ^¶ , Craig Bentzen , Eric Niesor , Brian Jackson and Keith E. Suckling

From the  Department of Vascular Biology, Smithkline Beecham Pharmaceuticals, The Frythe, Welwyn, Herts. AL6 9AR, United Kingdom, the ^¶ Medical Research Council Lipoprotein Team, Hammersmith Hospital, London W12 0HS, United Kingdom, and  Symphar Research Laboratories, 243 Route des Fayards, 1290 Versoix, Geneva, Switzerland

SR-12813 (tetra-ethyl 2-(3,5-di-tert-butyl-4-hydroxyphenyl)ethenyl-1,1-bisphosphonate) lowers plasma cholesterol in five species. In this paper we investigate the underlying mechanism using Hep G2 cells. SR-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 T1/2 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 T1/2 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.

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