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dc.contributor.authorBerkhout, Theo
dc.contributor.authorSimon, Helen M.
dc.contributor.authorPatel, Dilip D.
dc.contributor.authorBentzen, Craig
dc.contributor.authorNiesor, Eric
dc.contributor.authorJackson, Brian
dc.contributor.authorSuckling, Keith E.
dc.identifier.citationBerkhout , T , Simon , H M , Patel , D D , Bentzen , C , Niesor , E , Jackson , B & Suckling , K E 1996 , ' The novel cholesterol-lowering drug SR-12813 inhibits cholesterol synthesis via an increased degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase ' , Journal of Biological Chemistry , vol. 271 , no. 24 , pp. 14376-14382 .
dc.identifier.otherPURE: 7130419
dc.identifier.otherPURE UUID: b200a5e4-283d-4e73-ae87-af97285252a0
dc.identifier.otherScopus: 15844402429
dc.identifier.otherPubMed: 8662919
dc.description.abstractSR-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.en
dc.relation.ispartofJournal of Biological Chemistry
dc.titleThe novel cholesterol-lowering drug SR-12813 inhibits cholesterol synthesis via an increased degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductaseen
dc.contributor.institutionDepartment of Human and Environmental Sciences
dc.contributor.institutionSchool of Life and Medical Sciences
dc.contributor.institutionDepartment of Pharmacy
dc.contributor.institutionMedicinal and Analytical Chemistry
dc.description.statusPeer reviewed
rioxxterms.typeJournal Article/Review

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