Skip to main content
SpringerLink
Log in

Inhibition of Cholesterol Biosynthesis

  • Living reference work entry
  • First Online:
Drug Discovery and Evaluation: Pharmacological Assays

  • 609 Accesses

Abstract

The following steps are involved in cholesterol biosynthesis:

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Institutional subscriptions

Similar content being viewed by others

References and Further Reading

General Considerations on Cholesterol Biosynthesis

  • Abe I, Prestwich GD (1998) Development of new cholesterol-lowering drugs. Drug Dev Today 3:389–390

    Article  Google Scholar 

  • Abe I, Zheng YF, Prestwich GD (1998a) Mechanism based inhibitors and other active-site targeted inhibitors of oxidosqualene cyclase and squalene cyclase. J Enzyme Inhib 13:385–398

    Article  CAS  PubMed  Google Scholar 

  • Abe I, Zheng YF, Prestwich GD (1998b) Photoaffinity labeling of oxidosqualene cyclase and squalene cyclase by a benzophenone-containing inhibitor. Biochemistry 37:5779–5784

    Article  CAS  PubMed  Google Scholar 

  • Amin D, Rutledge RZ, Needle SN, Galczenski HF, Neuenschwander K, Scotese AC, Maguire MP, Bush RC, Hele DJ, Bilder GE, Perrone MH (1997) RPR 107393, a potent squalene synthase inhibitor and orally effective cholesterol-lowering agent: comparison with inhibitors of HMG-CoA reductase. J Pharmacol Exp Ther 281:746–752

    Google Scholar 

  • Bae S-H, Lee JN, Fitzky BU, Seong J, Paik Y-K (1999) Cholesterol biosynthesis from lanosterol. Molecular cloning, tissue distribution, expression, chromosomal location and regulation of rat 7-dehydrocholesterol reductase, a Smith-Lemli-Opitz syndrome-related protein. J Biol Chem 274:14624–14631

    Article  CAS  PubMed  Google Scholar 

  • Cattel L, Ceruti M, Balliano G, Viola F, Grosa G, Schuber F (1989) Drug design based on biosynthetic studies: synthesis, biological activity, and kinetics of new inhibitors of 2,3-oxidosqualene cyclase and squalene epoxidase. Steroids 53:363–391

    Article  CAS  PubMed  Google Scholar 

  • Dollis D, Schuber F (1994) Effects of a 2,3-oxidosqualene-lanosterol cyclase inhibitor 2,3:22,23-dioxidosqualene and 24,25-epoxycholesterol on the regulation of cholesterol biosynthesis in human hepatoma cell line HepG2. Biochem Pharmacol 48:49–57

    Article  CAS  PubMed  Google Scholar 

  • Eisele B, Budzinski R, Müller P, Maier R, Mark M (1997) Effects of a novel 2,3-oxidosqualene cyclase inhibitor on cholesterol biosynthesis and lipid metabolism in vivo. J Lipid Res 38:564–575

    CAS  PubMed  Google Scholar 

  • Gerst N, Schuber F, Viola F, Cattel L (1986) Inhibition of cholesterol biosynthesis in 3 T3 fibroblasts by 2-aza-2,3-dihydrosqualene, a rationally designed 2,3-oxidosqualene cyclase inhibitor. Biochem Pharmacol 35:4243–4250

    Article  CAS  PubMed  Google Scholar 

  • Goldstein JL, Brown MS (1990) Regulation of mevalonate pathway. Nature 343:425–430

    Google Scholar 

  • Grayson NA, Westkaemper RB (1988) Stable analogs of acyl adenylates. Inhibition of acetyl- and acyl-CoA synthetase by adenosine 5′-alkylphosphates. Life Sci 43:437–444

    Article  CAS  PubMed  Google Scholar 

  • Greenspan MD, Yudkowitz JB, Lo CYL, Chen JS, Alberts AW, Hunt VM, Chang MN, Yang SS, Thompson KL, Chiang YCP, Chabala JC, Monaghan RL, Schwartz RL (1987) Inhibition of hydroxymethylglutaryl-coenzyme A synthase by L-659,699. Proc Natl Acad Sci U S A 84:7488–7492

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Greenspan MD, Bull HG, Yudkovitz JB, Hanf DP, Alberts AW (1993) Inhibition of 3-hydroxy-3-methylglutaryl-CoA synthase and cholesterol biosynthesis by beta-lactone inhibitors and binding of these inhibitors to the enzyme. Biochem J 289(Pt 3):889–895

    PubMed Central  CAS  PubMed  Google Scholar 

  • Kourounakis AP, Matralis AN, Nikitakis A (2010) Design of more potent squalene synthase inhibitors with multiple activities. Bioorg Med Chem 18:7402–7412

    Article  CAS  PubMed  Google Scholar 

  • Mark M, Müller P, Maier R, Eisele B (1996) Effects of a novel 2,3-oxidosqualene cyclase inhibitor on the regulation of cholesterol biosynthesis in HepG2 cells. J Lipid Res 37:148–158

    CAS  PubMed  Google Scholar 

  • Menys VC, Durrington PN (2003) Squalene synthase inhibitors. Br J Pharmacol 139:881–882

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Miller LR, Pinkerton FT, Schroepfer GJ (1980) 5α-Cholest-8(14)-en-3β-ol-15-one, a potent inhibitor or sterol synthesis, reduces the levels of activity of enzymes involved in the synthesis and reduction of 3-hydroxy-3-methylglutaryl coenzyme A in CHO-K1 cells. Biochem Int 1:223–228

    CAS  Google Scholar 

  • Morand OH, Aebi JD, Dehmlow H, Ji Y-H, Gains N, Lengsfeld H, Himber J (1997) Ro 48–8071, a new 2,3-oxidosqualene:lanosterol cyclase inhibitor lowering plasma cholesterol in hamsters, squirrel monkeys, and minipigs: comparison to simvastin. J Lipid Res 38:373–390

    CAS  PubMed  Google Scholar 

  • Ness GC, Zhao Z, Keller RK (1994) Effect of squalene synthase inhibition on the expression of hepatic cholesterol biosynthesis enzymes, LDL receptor, and cholesterol 7-alpha-hydroxylase. Arch Biochem Biophys 311:277–285

    Article  CAS  PubMed  Google Scholar 

  • Rosenberg SH (1998) Squalene synthase inhibitors. Expert Opin Ther Pat 8:521–530

    Google Scholar 

  • Ryder NS (1992) Terbinafine: mode of action and properties of the squalene epoxidase inhibition. Br J Dermatol 126(Suppl 39):2–7

    Article  PubMed  Google Scholar 

  • Sen SE, Prestwich GD (1989) Squalene analogs containing isopropylidene mimics as potential inhibitors of pig liver squalene epoxidase and oxidosqualene cyclase. J Med Chem 32:2152–2158

    Article  CAS  PubMed  Google Scholar 

  • Sliskovic DR, Picard JA (1997) Squalene synthase inhibitors. Emerg Drugs 2:93–107

    Google Scholar 

  • Waterham HR, Wanders RJA (2000) Biochemical and genetic aspects of 7-dehydrocholesterol reductase and Smith-Lemli-Opitz syndrome. Biochim Biophys Acta 1529:340–356

    Article  CAS  PubMed  Google Scholar 

General Considerations on HMG-CoA-Reductase

  • Clinkenbeard KD, Sugiyama T, Reed WD, Lane MD (1975) Cytoplasmatic 3-hydroxy-3-methylglutaryl coenzyme A synthase from liver. Purification, properties, and role in cholesterol synthesis. J Biol Chem 250:3124–3135

    CAS  Google Scholar 

  • Flint OP, Masters BA, Gregg RE, Durham SK (1997) Inhibition of cholesterol synthesis by squalene synthase inhibitors does not induce myotoxicity in vitro. Toxicol Appl Pharmacol 145:91–98

    Article  CAS  PubMed  Google Scholar 

  • Goldstein JL, Brown MS (1990) Regulation of the mevalonate pathway. Nature 343:425–430

    Google Scholar 

  • Gotto AM (1990) Pravastatin: a hydrophilic inhibitor of cholesterol synthesis. J Drug Dev 3:155–161

    Google Scholar 

  • Graham DJ, Staffa JA, Shatin D, Andrade SE, Schech SD, Grenade LL, Gurwitz JH, Chan KA, Goodman MJ, Platt R (2004) Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs. J Am Med Assoc 2992:2585–2590

    Article  Google Scholar 

  • Jendralla H, Baader E, Bartmann W, Beck G, Bergmann A, Granzer E, von Kerekjarto B, Kesseler K, Krause R, Schubert W, Wess G (1990) Synthesis and biological activity of new HMG-CoA reductase inhibitors. 2. Derivatives of 7-(1H-pyrrol-3-yl)-substituted-3,5-dihydroxyhept-6(E)-enoic(−heptanoic) acids. J Med Chem 33:61–70

    Article  CAS  PubMed  Google Scholar 

  • Jungnickel PW, Cantral KA, Maloley PA (1992) Pravastin: a new drug for the treatment of hypercholesterinemia. Clin Pharm 11:677–689

    CAS  PubMed  Google Scholar 

  • Klotz U (2003) Pharmacological comparison of the statins. Arzn Forsch/Drug Res 53:605–611

    CAS  Google Scholar 

  • Krause R, Neubauer H, Leven M, Kesseler K (1990) Inhibition of cholesterol synthesis in target tissues and extrahepatic organs after administration of HMG-CoA reductase inhibitors in normolipidaemic rats: organ selectivity and time course of the inhibition. J Drug Dev 3(Suppl 1):255–257

    Google Scholar 

  • Mauro VF, MacDonald JL (1991) Simvastatin: a review of its pharmacology and clinical use. DICP Ann Pharmacother 25:257–264

    CAS  Google Scholar 

  • Parish EJ, Nanduri VBB, Kohl HH, Taylor FR (1986) Oxysterols: chemical synthesis, biosynthesis and biological activities. Lipids 21:27–30

    Article  CAS  PubMed  Google Scholar 

  • Rodwell VW, Nordstrom JL, Mitschelen JJ (1976) Regulation of HMG-CoA reductase. In: Paoletti R, Kritchevsky D (eds) Advances in lipid research, vol 14. Academic, New York, pp 1–74

    Google Scholar 

  • Saito Y, Kitahara MKS, Sakashita MSK, Toyoda KSK, Shibazaki TSK (1993) Novel inhibitors of atherosclerotic intimal thickening. Curr Opin Ther Pat 3:1241–1242

    Article  Google Scholar 

  • Sakamoto K, Kimura J (2013) Mechanism of statin-induced rhabdomyolysis. J Pharmacol Sci 123:289–294

    Article  CAS  PubMed  Google Scholar 

  • Scott WA (1990) Hydrophilicity and the differential pharmacology of pravastin. In: Wood C (ed) Lipid management: pravastin and the differential pharmacology of HMG-CoA reductase inhibitors. Round Table Series No 16, Royal Society of Medicine Service, pp 17–25

    Google Scholar 

  • Shapiro DJ, Rodwell VW (1969) Diurnal variation and cholesterol regulation of hepatic HMG-CoA reductase activity. Biochem Biophys Res Commun 37:687–872

    Google Scholar 

  • Shefer S, Hauser S, Lapar V, Mosbach EH (1972) Diurnal variation of HMG CoA reductase activity in rat intestine. J Lipid Res 13:571–573

    CAS  PubMed  Google Scholar 

  • Sirtori CR (1990) Pharmacology and mechanism of action of the new HMG-CoA reductase inhibitors. Pharmacol Res 22:555–563

    Article  CAS  PubMed  Google Scholar 

  • Soma MR, Corsini A, Paoletti R (1992) Cholesterol and mevalonic acid modulation in cell metabolism and multiplication. Toxicol Lett 64(65):1–15

    Article  PubMed  Google Scholar 

  • Trzaskos JM, Magolda RL, Favata MF, Fischer RT, Johnson PR, Chen HW, Ko SS, Leonard DA, Gaylor JL (1993) Modulation of 3-hydroxy-3-methylglutaryl-CoA reductase by 15α-fluorolanost-7-en-3β-ol. A mechanism-based inhibitor of cholesterol biosynthesis. J Biol Chem 268:22591–22599

    CAS  PubMed  Google Scholar 

  • Tsujita Y (1990a) A potent HMG-CoA reductase inhibitor, pravastatin sodium. Tissue selective inhibition of cholesterogenesis and preventive effect on atherosclerosis in WHHL rabbits. J Drug Dev 3(Suppl 1):155–159

    Google Scholar 

  • Tsujita Y (1990b) HMG-CoA reductase inhibitors. J Jpn Atheroscler Soc 18:165–171

    Google Scholar 

Inhibition of the Isolated Enzyme HMG-CoA-Reductase in Vitro

  • Avigan J, Bhathena SJ, Schreiner ME (1975) Control of sterol synthesis and of hydroxymethylglutaryl CoA reductase in skin fibroblasts grown from patients with homozygous type II hyperlipoproteinemia. J Lipid Res 16:151–154

    CAS  PubMed  Google Scholar 

  • Baker FC, Schooley DA (1979) Analysis and purification of acyl coenzyme A thioesters by reversed-phase ion-pair liquid chromatography. Anal Biochem 94:417–424

    Article  CAS  PubMed  Google Scholar 

  • Heller RA, Gould RG (1973) Solubilization and partial purification of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase. Biochem Biophys Res Commun 50:859–865

    Article  CAS  PubMed  Google Scholar 

  • Kramer W, Wess G, Enhsen A, Bock K, Falk E, Hoffmann A, Neckermann G, Gantz D, Schulz S, Nickau B, Petzinger E, Turley S, Dietschy JM (1994) Bile acid derived HMG-CoA reductase inhibitors. Biochim Biophys Acta 1227:137–154

    Article  PubMed  Google Scholar 

  • Kubo M, Strott CA (1987) Differential activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase in zones of the adrenal cortex. Endocrinol 120:214–221

    Article  CAS  Google Scholar 

  • Parker RA, Clark RW, Sit SY, Lanier TL, Grosso RA, Wright JJ (1990) Selective inhibition of cholesterol synthesis in liver versus extrahepatic tissues by HMG-CoA reductase inhibitors. J Lipid Res 31:1271–1282

    Google Scholar 

  • Philipp BW, Shapiro DJ (1979) Improved methods for the assay and activation of 3-hydroxy-3-methylglutaryl coenzyme A reductase. J Lipid Res 20:588–593

    CAS  PubMed  Google Scholar 

  • Wess G, Kramer W, Han XB, Bock K, Enhsen A, Glombik H, Baringhaus KH, Böger G, Urmann M, Hoffmann A, Falk E (1994) Synthesis and biological activity of bile acid-derived HMG-CoA reductase inhibitors. The role of the 21-methyl in recognition of HMG-CoA reductase and the ileal bile acid transport system. J Med Chem 37:3240–3246

    Article  CAS  PubMed  Google Scholar 

Inhibition of the Incorporation of 14C-Sodium Acetate into Cholesterol in Isolated Liver Cells

  • Beck G, Kesseler K, Baader E, Bartmann W, Bergmann A, Granzer E, Jendralla H, von Kerekjarto B, Krause R, Paulus E, Schubert W, Wess G (1990) Synthesis and biological activity of new HMG-CoA reductase inhibitors. 1. Lactones of pyridine- and pyrimidine-substituted 3,5-dihydroxy-6-heptenoic (heptanoic) acids. J Med Chem 33:52–60

    Google Scholar 

  • Chen HW, Kandutsch AA (1976) Effects of cholesterol derivatives on sterol biosynthesis. In: Day CE (ed) Atherosclerosis drug discovery. Plenum, New York/London, pp 405–417

    Chapter  Google Scholar 

  • Gebhardt R (1993) Multiple inhibitory effects of garlic extracts on cholesterol biosynthesis in hepatocytes. Lipids 28:613–619

    Article  CAS  PubMed  Google Scholar 

  • Gotto AM (1990) Pravastatin: a hydrophilic inhibitor of cholesterol synthesis. J Drug Dev 3:155–161

    Google Scholar 

  • Greenspan MD, Yudkovitz JB, Chen JS, Hanf DP, Chang MN, Chiang PYC, Chabala JC, Alberts AW (1989) The inhibition of cytoplasmatic acetoacetyl-CoA thiolase by a triyne carbonate (L-660,631). Biochem Biophys Res Commun 163:548–553

    Article  CAS  PubMed  Google Scholar 

  • Hidaka Y, Hotta H, Nagata Y, Iwasawa Y, Horie M, Kamei T (1991) Effect of a novel squalene epoxidase inhibitor, NB-598, on the regulation of cholesterol metabolism in HEP G2 cells. J Biol Chem 266:13171–13177

    CAS  PubMed  Google Scholar 

  • Parker RA, Clark RW, Sit SY, Lanier TL, Grosso RA, Wright JJ (1990) Selective inhibition of cholesterol synthesis in liver versus extrahepatic tissues by HMG-CoA reductase inhibitors. J Lipid Res 31:1271–1282

    Google Scholar 

  • Pearce BC, Parker RA, Deason ME, Qureshi AA, Kim Wright JJ (1992) Hypocholesterolemic activity of synthetic and natural tocotrienols. J Med Chem 35:3595–3606

    Article  CAS  PubMed  Google Scholar 

  • Raiteri M, Amaboldi L, McGeady P, Gelb MH, Veri D, Tagliabue C, Quarato P, Ferraboschi P, Santaniello E, Paoletti R, Fumagalli R, Corsini A (1997) Pharmacological control of mevalonate pathway: effect on arterial smooth muscle cell proliferation. J Pharmacol Exp Ther 281:1144–1153

    CAS  PubMed  Google Scholar 

  • Scott WA (1990) Hydrophilicity and the differential pharmacology of pravastin. In: Wood C (ed) Lipid management: pravastin and the differential pharmacology of HMG-CoA reductase inhibitors. Royal Society of Medicine Services, London, pp 17–25

    Google Scholar 

  • Shaw MK, Newton RS, Sliskovic DR, Roth BD, Ferguson E, Krause BR (1990) HEP-G2 cells and primary rat hepatocytes differ in their response to inhibitors of HMG-CoA reductase. Biochem Biophys Res Commun 170:726–734

    Article  CAS  PubMed  Google Scholar 

  • Tsujita Y (1990c) A potent HMG-CoA reductase inhibitor, pravastatin sodium. Tissue selective inhibition of cholesterogenesis and preventive effect on atherosclerosis in WHHL rabbits. J Drug Dev 3(Suppl 1):155–159

    Google Scholar 

Ex Vivo Inhibition of Cholesterol Biosynthesis in Isolated Rat Liver Slices

  • Amin D, Gustafson SK, Weinacht JM, Cornell SA, Neuenschwander K, Kosmider B, Scotese AC, Regan JR, Perrone MH (1993) RG 12561 (Dalvastatin): a novel synthetic inhibitor of HMG-CoA reductase and cholesterol-lowering agent. Pharmacology 46:13–22

    Article  CAS  PubMed  Google Scholar 

  • Beck G, Kesseler K, Baader E, Bartmann W, Bergmann A, Granzer E, Jendralla H, von Kerekjarto B, Krause R, Paulus E, Schubert W, Wess G (1990) Synthesis and biological activity of new HMG-CoA reductase inhibitors. 1. Lactones of pyridine- and pyrimidine-substituted 3,5-dihydroxy-6-heptenoic (heptanoic) acids. J Med Chem 33:52–60

    Google Scholar 

  • Bocan TMA, Ferguson E, McNally W, Uhlendorf PD, Mueller SB, Dehart P, Sliskovic DR, Roth BD, Krause BR, Newton RS (1992) Hepatic and non hepatic sterol synthesis and tissue distribution of a liver selective HMG-CoA reductase inhibitor, CI-981: comparison with selected HMG-CoA reductase inhibitors. Biochim Biophys Acta 1123:133–144

    Article  CAS  PubMed  Google Scholar 

  • Brown MS, Goldstein JL, Dietschy JM (1979) Active and inactive forms of 3-hydroxyx-3-methylglutaryl coenzyme A reductase in the liver of the rat. J Biol Chem 254:5144–5149

    CAS  PubMed  Google Scholar 

  • Koga T, Shimada Y, Kuroda M, Tsujita Y, Hasegawa K, Yamazaki M (1990) Tissue-selective inhibition of cholesterol synthesis in vivo by pravastatin sodium, a 3-hydroxy-3-methylglutaryl-coenzym A reductase inhibitor. Biochim Biophys Acta 1045:115–120

    Article  CAS  PubMed  Google Scholar 

  • Mosley ST, Kalinowski SS, Schafer BL, Tanaka RD (1989) Tissue-selective acute effects of inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase on cholesterol biosynthesis in lens. J Lipid Res 30:1411–1420

    CAS  PubMed  Google Scholar 

Effect of HMG-CoA-Reductase Inhibitors in Vivo

  • Abletshauser C, Klüßendorf D, Schmidt A, Winkler K, März W, Buddecke E, Malmstan M, Siegel G (2002) Biosensing of arteriosclerotic nanoplaque formation and interaction with an HMG CoA reductase inhibitor. Acta Physiol Scand 176:131–145

    Article  CAS  PubMed  Google Scholar 

  • Aoki T, Yoshinaka Y, Yamazaki H, Suzuki H, Tamaki T, Sato F, Kitahara M, Saito Y (2002) Triglyceride-lowering effect of pivastatin in a rat model of postprandial lipemia. Eur J Pharmacol 444:107–113

    Article  CAS  PubMed  Google Scholar 

  • Bocan TMA, Mazur MJ, Mueller SB, Brown EQ, Sliskovic DR, O’Brien PM, Creswell MW, Lee H, Uhlendorf PD, Roth BD, Newton RS (1994) Antiatherosclerotic activity of inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase in cholesterol-fed rabbits: a biochemical and morphological evaluation. Atherosclerosis 111:127–142

    Article  CAS  PubMed  Google Scholar 

  • Booth RGF, Martin JF, Honey AC, Hassall DG, Beesley JE, Moncada S (1989) Rapid development of atherosclerotic lesions in the rabbit carotid artery induced by perivascular manipulation. Atherosclerosis 76:257–268

    Article  CAS  PubMed  Google Scholar 

  • Delsing DJ, Jukema JW, van de Wiel MA, Emeis JJ, van der Laarse A, Havekes LM, Princen HM (2003) Differential effects of amlodipin and atorvastin treatment and their combination on atherosclerosis in ApoE*3-Leiden transgenic mice. J Cardiovasc Pharmacol 42:63–70

    Article  CAS  PubMed  Google Scholar 

  • Ha YC, Barter PJ (1985) Rapid separation of plasma lipoproteins by gel permeation chromatography on agarose gel Superose 6B. J Chromatogr 341:154–159

    Article  CAS  PubMed  Google Scholar 

  • Holdgate GA, Ward WH, McTaggart F (2003) Molecular mechanism for inhibition of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase by rosuvastatin. Biochem Soc Trans 31:528–531

    Article  CAS  PubMed  Google Scholar 

  • Johnston TP, Nguyen LB, Chu WA, Shefer S (2001) Potency of selected statin drugs in a new mouse model of hyperlipidemia and atherosclerosis. Int J Pharm 229:75–86

    Article  CAS  PubMed  Google Scholar 

  • Kasim SE, Elovson J, Khilnani S, Almario RU, Jen KLC (1993) The effect of lovastatin on the secretion of very low density lipoprotein lipids and apolipoprotein B in the hypertriglyceridemic Zucker obese rat. Atherosclerosis 104:147–152

    Article  CAS  PubMed  Google Scholar 

  • Krause BR, Newton SB (1995) Lipid-lowering activity of atorvastatin and lovostatin in rodent species: triglyceride-lowering in rats correlates with efficacy in LDL animals. Atherosclerosis 117:237–244

    Article  CAS  PubMed  Google Scholar 

  • Soma MR, Donetti E, Paroline C, Mazzini G, Ferrari C, Fumagalli R, Paoletti R (1993) HMG-CoA reductase inhibitors. In vivo effects on carotid intimal thickening in normocholesterolemic rabbits. Arterioscler Thromb 13:571–578

    Article  CAS  PubMed  Google Scholar 

  • Tsujita Y (1990d) A potent HMG-CoA reductase inhibitor, pravastatin sodium. Tissue selective inhibition of cholesterogenesis and preventive effect on atherosclerosis in WHHL rabbits. J Drug Dev 3(Suppl 1):155–159

    Google Scholar 

  • Tsujita Y, Kuroda M, Shimada Y, Tanzawa K, Arai M, Kaneko I, Tanaka M, Masuda H, Tarumi C, Watanabe Y, Fujii S (1986) CS-514, a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase: tissue-selective inhibition of sterol synthesis and hypolipidemic effect on various animal species. Biochim Biophys Acta 877:50–60

    Article  CAS  PubMed  Google Scholar 

  • Ugawa T, Kakuta H, Moritani H, Shikama H (2002) Experimental model of escape phenomenon in hamsters and the effectiveness of YM-53601 in the model. Br J Pharmacol 135:1572–1578

    Google Scholar 

  • Watanabe Y (1980) Serial inbreeding of rabbits with hereditary hyperlipidemia (WHHL)-rabbit. Incidence and development of atherosclerosis and xanthoma. Atherosclerosis 36:261–268

    Article  CAS  PubMed  Google Scholar 

  • Watanabe Y, Ito T, Shiomi M (1985) The effect of selective breeding on the development of coronary atherosclerosis in WHHL rabbits. An animal model for familial hypercholesterolemia. Atherosclerosis 56:71–79

    Article  CAS  PubMed  Google Scholar 

  • Watanabe Y, Ito T, Shiomi M, Tsujita Y, Kuroda M, Arai M, Fukami M, Tamura A (1988) Preventive effect of pravastatin sodium, a potent inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, on coronary atherosclerosis and xanthoma in WHHL rabbits. Biochim Biophys Acta 960:294–302

    Article  CAS  PubMed  Google Scholar 

  • Yokota N, O’Donnell M, Daniels F, Burne-Taney M, Keane W, Kasiske B, Rabb H (2003) Protective effect of HMG CoA reductase inhibitor on experimental renal ischemia-reperfusion injury. Am J Nephrol 23:13–17

    Article  CAS  PubMed  Google Scholar 

Influence of Statins on Endothelial Nitric Oxide Synthase

  • Amin-Hanjani S, Stagliano NE, Yamada M, Huang PL, Liao JK, Moskowitz MA (2001) Mevastatin, an HMG-CoA reductase inhibitor, reduces stroke damage and upregulates endothelial nitric oxide synthase in mice. Stroke 32:980–986

    Article  CAS  PubMed  Google Scholar 

  • Baetta R, Camera M, Comparato C, Altana C, Ezekowitz MD, Tremoli E (2002) Fluvastatin reduces tissue factor expression and macrophage accumulation in carotid lesions of cholesterol-fed rabbits in the absence of lipid lowering. Arterioscler Thromb Vasc Biol 22:692–698

    Article  CAS  PubMed  Google Scholar 

  • Balakumar P, Kathuria S, Taneja G, Kalra S, Mahadevan N (2012) Is targeting eNOS a key mechanistic insight of cardiovascular defensive potentials of statins? J Mol Cell Cardiol 52:83–92

    Article  CAS  PubMed  Google Scholar 

  • Ikeda Y, Young LH, Lefer AM (2003) Rosuvastin, a new HMG-CoA reductase inhibitor, protects ischemic reperfused myocardium in normocholesterolemic rats. J Cardiovasc Pharmacol 41:649–656

    Article  CAS  PubMed  Google Scholar 

  • Jones SP, Gibson MF, Rimmer DM, Gibson TM, Sharp BR, Lefer DJ (2002) Direct vascular and cardioprotective effects of rosuvastatin, a new HMG-CoA reductase inhibitor. J Am Coll Cardiol 40:1172–1178

    Article  CAS  PubMed  Google Scholar 

  • Kano H, Hayashi T, Sumi D, Esaki T, Asai Y, Thakur NK, Jayachandran M, Iguchi A (1999) A HMG-CoA reductase inhibitor improved regression of atherosclerosis in the rabbit aorta without affecting serum lipid levels: possible relevance of up-regulation of endothelial NO synthase mRNA. Biochem Biophys Res Commun 259:414–419

    Article  CAS  PubMed  Google Scholar 

  • Kelm M, Dahmann R, Wink D, Feelisch M (1997) The nitric oxide/superoxide assay. J Biol Chem 272:9922–9932

    Article  CAS  PubMed  Google Scholar 

  • Kumai T, Oonuma S, Matsumoto N, Takeba Y, Taniguchi R, Kamio K, Miyazu O, Koitabashi Y, Sekine S, Tadokoro M, Kobayashi S (2004) Anti-lipid deposition effect of HMG-CoA reductase inhibitor, pitavastin, in a rat model of hypertension and hypercholesterolemia. Life Sci 74:2129–2142

    Article  CAS  PubMed  Google Scholar 

  • Laufs U, Gertz K, Dirnagl U, Böhm M, Nickenig G, Endres M (2002) Rosuvastatin, a new HMG-CoA reductase inhibitor, upregulates endothelial nitric oxide synthase and protects from ischemic stroke in mice. Brain Res 942:23–30

    Article  CAS  PubMed  Google Scholar 

  • Mitani H, Egashira K, Ohashi N, Yoshikawa M, Niwa S, Nonomura K, Nakashima A, Kimura M (2003a) Preservation of endothelial function by the HMG-CoA reductase inhibitor fluvastatin through its lipid-lowering independent antioxidant properties in atherosclerotic rabbits. Pharmacology 68:121–130

    Article  CAS  PubMed  Google Scholar 

  • Mitani H, Egashira K, Kimura M (2003b) HMG-Ca reductase inhibitor, fluvastatin, has cholesterol-lowering independent “direct” effects on atherosclerotic vessels in high cholesterol diet-fed rabbits. Pharmacol Res 48:417–427

    Article  CAS  PubMed  Google Scholar 

  • Parker RA, Clark RW, Sit SY, Lanier TL, Grosso RA, Wright JJ (1990c) Selective inhibition of cholesterol synthesis in liver vs. extrahepatic tissues by HMG CoA reductase inhibitors. J Lipid Res 31:1271–1282

    CAS  PubMed  Google Scholar 

  • Parker RA, Huang Q, Tesfamariam B (2003) Influence of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors on endothelial nitric oxide synthase and the formation of oxidants in the vasculature. Atherosclerosis 169:19–29

    Article  CAS  PubMed  Google Scholar 

  • Rikitake Y, Kawashima S, Takeshita S, Yamashita T, Azumi H, Yasuhara M, Nishi H, Inoue N, Yokoyama M (2001) Anti-oxidative properties of fluvastatin, an HMG-CoA reductase inhibitor, contribute to prevention of atherosclerosis in cholesterol-fed-rabbits. Atherosclerosis 154:87–96

    Article  CAS  PubMed  Google Scholar 

  • Sata M, Nishimatsu H, Suzuki E, Sugiura S, Yoshizumi M, Ouchi Y, Hirata Y, Ngai R (2001) Endothelial nitric oxide synthase is essential for the HMG-CoA reductase inhibitor cerivastatin to promote collateral growth ion response to ischemia. FASEB J 15:2530–2532

    CAS  PubMed  Google Scholar 

  • Shimizu K, Aikawa M, Takayama K, Libby P, Mitchell RN (2003) Direct anti-inflammatory mechanisms contribute to attenuation of experimental allograft arteriosclerosis by statins. Circulation 108:2113–2120

    Article  CAS  PubMed  Google Scholar 

  • Sumi D, Hayashi T, Thakur NK, Jayachandran M, Asai Y, Kano H, Matsui H, Iguchi A (2001) A HMG-CoA reductase inhibitor possesses a potent anti-atherosclerotic effect other than lipid lowering effects – the relevance of endothelial nitric oxide reductase and superoxide anion scavenging action. Atherosclerosis 155:347–357

    Article  CAS  PubMed  Google Scholar 

  • Walter DH, Dimmeler S, Zeiher AM (2004) Effects of statins on endothelium and endothelial progenitor cell recruitment. Semin Vasc Med 4:385–393

    Article  PubMed  Google Scholar 

  • Wassmann S, Nickenig G (2003) Interrelationship of free oxygen radicals and endothelial dysfunction – modulation by statins. Endothelium 10:23–33

    Article  CAS  PubMed  Google Scholar 

  • Yamamoto T, Takeda K, Harada S, Nakata T, Azuma A, Sasaki S, Nakagawa M (2003) HMG-CoA reductase inhibitor enhances inducible nitric oxide synthase expression in rat vascular smooth muscle cell; involvement of the Rho/Rho kinase pathway. Atherosclerosis 166:213–222

    Article  CAS  PubMed  Google Scholar 

Inhibition of Squalene Synthase

  • Amano Y, Nishimoto T, Tozawa R, Ishikawa E, Imura Y, Sugiyama Y (2003) Lipid-lowering effects of TAK-475, a squalene synthase inhibitor: animal models of familial hypercholesterolemia. Eur J Pharmacol 466:155–161

    Article  CAS  PubMed  Google Scholar 

  • Amin D, Cornell SA, Gustafson DK, Needle SJ, Ullrich JW, Bilder GE, Perrone MH (1992) Biphosphonates used for the treatment of bone disorders inhibit squalene synthase and cholesterol biosynthesis. J Lipid Res 33:1657–1663

    CAS  PubMed  Google Scholar 

  • Amin D, Rutledge RZ, Needle SN, Hele DJ, Neuenschwander K, Bush RC, Bilder GE, Perrone MH (1996) RPR 101821, a new potent cholesterol-lowering agent: inhibition of squalene synthase and 7-dehydrocholesterol reductase. Naunyn Schmiedebergs Arch Pharmacol 353:233–240

    Article  CAS  PubMed  Google Scholar 

  • Amin D, Rutledge RZ, Needle SN, Hele DJ, Galczenski HF, Neuenschwander K, Scotese AC, Maguire MP, Bush RC, Hele DJ, Bilder GE, Perrone MH (1997) RPR 101821, a potent squalene synthase inhibitor and orally effective cholesterol-lowering agent: comparison with inhibitors of HMG-CoA reductase. J Pharmacol Exp Ther 281:746–752

    Google Scholar 

  • Baxter A, Fitzgerald BJ, Hutson JL, McCarthy AD, Motteram JM, Ross BC, Sapra M, Snowden MA, Watson NS, Williams RJ, Wright C (1992) Squalestatin 1, a potent inhibitor of squalene synthase, which lowers cholesterol in vivo. J Biol Chem 267:11705–11708

    CAS  PubMed  Google Scholar 

  • Biller SA, Forster C, Gordon EM, Harrity T, Rich LC, Marretta J, Ciosek CP (1991a) Isoprenyl phosphinylformates: new inhibitors of squalene synthetase. J Med Chem 34:1912–1914

    Article  CAS  PubMed  Google Scholar 

  • Biller SA, Sofia MJ, DeLange B, Forster C, Gordon EM, Harrity T, Rich LC, Ciosek CP (1991b) The first potent inhibitor of squalene synthase: a profound contribution of an ether oxygen to inhibitor-enzyme interaction. J Am Chem Soc 113:8522–8524

    Article  CAS  Google Scholar 

  • Chan C, Andreotti D, Cox B, Dymock BW, Hutson JL, Keeling SE, McCarthy AD, Procopiou PA, Ross BC, Sareen M, Scicinski JJ, Sharatt PJ, Snowden MA, Watson MS (1996) The squalestatins: decarboxy and 4-deoxy analogues as potent squalene synthase inhibitors. J Med Chem 39:207–215

    Article  CAS  PubMed  Google Scholar 

  • Ciosek CP Jr, Magnin DR, Harrity DW, Logan JV, Dickson JK Jr, Gordon EM, Hamilton KA, Jolibois KG, Kunselman LK, Lawrence RM (1993) Lipophilic 1,1-bisphosphonates are potent squalene synthase inhibitors and orally active cholesterol lowering agents in vivo. J Biol Chem 268:24832–24837

    CAS  PubMed  Google Scholar 

  • Dufresne C, Jones ETT, Omstead MN, Bergstrom JD, Wilsin KE (1996) Novel zaragozic acids from Leptodontidium elatius. J Nat Prod 59:52–54

    Article  CAS  Google Scholar 

  • Harris GH, Dufresne C, Joshua H, Koch LA, Zink DL, Salmon PM, Goklen KE, Kurtz MM, Rew DJ, Bergstrom JD, Wilson KE (1995) Isolation, structure determination and squalene synthase activity of L-731,120 and L-731,128, alkyl citrate analogs of zaragozic acids A and B. Bioorg Med Chem Lett 5:2403–2408

    Article  CAS  Google Scholar 

  • Hiyoshi H, Yanagimachi M, Ito M, Ohtsuka I, Yoshida I, Saeki T, Tanaka H (2000) Effect of ER-27856, a novel squalene synthase inhibitor, on plasma cholesterol in monkeys: comparison with 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors. J Lipid Res 41:1136–1144

    CAS  PubMed  Google Scholar 

  • Hiyoshi H, Yanagimachi M, Ito M, Yasuda N, Okada T, Ikuda H, Shinmyo D, Tanaka K, Kuruso Y, Yoshida I, Saeki T, Tanaka H (2003) Squalene synthase inhibitors suppress triglyceride biosynthesis through the farnesol pathway in hepatocytes. J Lipid Res 44:128–135

    Article  CAS  PubMed  Google Scholar 

  • Ishihara T, Kakuta H, Moritani H, Ugawa T, Sakamoto S, Tsukamoto S, Yanagishawa I (2003) Syntheses and biological evaluation of novel quinuclidine derivatives as squalene synthase inhibitors. Bioorg Med Chem 11:2403–2414

    Article  CAS  PubMed  Google Scholar 

  • Lindsey S, Harwood HJ (1995) Inhibition of mammalian squalene synthase activity by zaragozic acid A is a result of competitive inhibition followed by mechanism-based irreversible inactivation. J Biol Chem 270:9083–9096

    Article  CAS  PubMed  Google Scholar 

  • McTaggart F, Brown GR, Davidson RG, Freeman S, Holdgate GA, Mallion KB, Mirrlees DJ, Smith GJ, Ward WH (1996) Inhibition of squalene synthase of rat liver by novel 3′ substituted quinuclidines. Biochem Pharmacol 51:1477–1487

    Article  CAS  PubMed  Google Scholar 

  • Nishimoto T, Amano Y, Tozawa R, Ishikawa E, Imura Y, Yukimasa H, Sugiyama Y (2003) Lipid-lowering properties of TAK-475, a squalene synthase inhibitor in vivo and in vitro. Br J Pharmacol 139:911–918

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Oehlschlager AC, Singh SM, Sharma S (1991) Squalene synthetase inhibitors: synthesis of sulfonium ion mimics of the carbocationic intermediates. J Org Chem 56:3856–3861

    Article  CAS  Google Scholar 

  • Rosenberg SH (1998) Squalene synthase inhibitors. Expert Opin Ther Pat 8:521–530

    Google Scholar 

  • Sliskovic DR, Picard JA (1997) Squalene synthase inhibitors. Emerg Drugs 2:93–107

    Google Scholar 

  • Trapani L, Segatto M, Ascenzi P, Pallottini V (2011) Potential role of nonstatin cholesterol lowering agents. IUBMB Life 63:964–971

    Google Scholar 

  • Ugawa T, Kakuta H, Moritani H, Matsuda K, Ishihara T, Yamaguchi M, Naganuma S, Iizumi Y, Shikama H (2000) YM-53601, a novel squalene synthase inhibitor, reduces plasma cholesterol and triglyceride levels in several animal species. Br J Pharmacol 131:63–70

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Ugawa T, Kakuta H, Inagaki O (2002) Effect of YM-53691, a novel squalene synthase inhibitor, on the clearance rate ofplasma LDL and VLDL in hamsters. Br J Pharmacol 137:561–569

    Google Scholar 

  • Ugawa T, Kakuta H, Moritani H, Inagaki O, Shikama H (2003) YM-53601. a novel squalene synthase inhibitor, suppresses lipogenic biosynthesis and lipid secretion in rodents. Br J Pharmacol 139:140–146

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Vaidya S, Bostedor R, Kurtz MM, Bergstrom JD, Bansal VS (1998) Massive production of farnesol-derived dicarboxylic acids in mice treated with the squalene synthase inhibitor zaragozic acid A. Arch Biochem Biophys 355:84–92

    Article  CAS  PubMed  Google Scholar 

Inhibition of Squalene Epoxidase

  • Chugh A, Ray A, Gupta JB (2003) Squalene epoxidase as hypocholesterolemic drug revisited. Prog Lipid Res 42:37–50

    Article  CAS  PubMed  Google Scholar 

  • Ghirlanda G, Oradei A, Manto A, Lippa S, Uccioli L, Caputo S, Greco AV, Littarru GP (1993) Evidence of plasma CoQ10-lowering effect by HMG-CoA reductase inhibitors. A double-blind, placebo-controlled study. J Clin Pharmacol 33:226–229

    Article  CAS  PubMed  Google Scholar 

  • Gotteland JP, Loubat C, Planty B, Junquero D, Delhon A, Halazy S (1998) Sulfonamide derivatives of benzylamine block cholesterol biosynthesis in HepG-2 cells: a new type of squalene epoxidase inhibitors. Bioorg Med Chem Lett 8:1337–1342

    Article  CAS  PubMed  Google Scholar 

  • Grieveson LA, Ono T, Sakakibara J, Derrick JP, Dickinson JM, McMahon A, Higson SPJ (1997) A simplified squalene epoxidase assay based on an HPCL separation and time-dependent UV/visible determination of squalene. Anal Biochem 252:19–23

    Article  CAS  PubMed  Google Scholar 

  • Hidaka Y, Sato T, Kamei T (1990) Regulation of squalene epoxidase in HepG2 cells. J Lipid Res 31:2087–2094

    CAS  PubMed  Google Scholar 

  • Hikada Y, Hotta H, Nagata Y, Iwasawa Y, Horie M, Kamei T (1991) Effect of a novel squalene epoxidase inhibitor, NB-598, on the regulation of cholesterol metabolism in HepG2 cells. J Biol Chem 266:13171–13177

    Google Scholar 

  • Horie M, Tsuchiya Y, Hayashi M, Iida Y, Iwasawa Y, Nagata Y, Sawasaki Y, Fukuzumi H, Kitani K, Kamei T (1990) NB-598: a potent competitive inhibitor of squalene epoxidase. J Biol Chem 265:18075–18078

    CAS  PubMed  Google Scholar 

  • Horie M, Sawasaki Y, Fukuzumi H, Watanabe K, Iuzuka Y, Tsuchiya Y, Kamei T (1991) Hypolipidemic effects of NB-598 in dogs. Atherosclerosis 88:183–192

    Article  CAS  PubMed  Google Scholar 

  • Moore WR, Schatzman GL, Jarvi ET, Gross RS, McCarthy JR (1992) Terminal difluoro olefin analogues of squalene are time-dependent inhibitors of squalene epoxidase. J Am Chem Soc 114:360–361

    Article  CAS  Google Scholar 

  • Sawada M, Matsuo M, Hagihara H, Tenda N, Nagayoshi A, Okumura H, Washizuka KI, Seki J, Goto T (2001) Effect of FR194738, a potent inhibitor of squalene epoxidase, on cholesterol metabolism in HepG2 cells. Eur J Pharmacol 431:11–16

    Article  CAS  PubMed  Google Scholar 

  • Sawada M, Washizuka K, Okumura H (2004) Synthesis and biological activity of a novel squalene epoxidase inhibitor, FR194738. Bioorg Med Chem Lett 14:633–637

    Google Scholar 

  • Tai HH, Bloch K (1972) Squalene epoxidase of rat liver. J Biol Chem 247:3767–3773

    CAS  PubMed  Google Scholar 

  • Trapani L, Segatto M, Ascenzi P, Pallottini V (2011) Potential role of nonstatin cholesterol lowering agents. IUBMB Life 63:964–971

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Physiology, Université de Strasbourg, UMR CNRS 7213, 74 route du Rhin, CS 60024, 67401, Illkirch Cedex, France

    Philippe Boucher

  2. Johann Wolfgang Goethe-Universität Frankfurt am Main, Senckenberganlage 31, 60325, Frankfurt am Main, Germany

    Hans Gerhard Vogel

Authors
  1. Philippe Boucher
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hans Gerhard Vogel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Philippe Boucher .

Editor information

Editors and Affiliations

  1. Dieburg, Germany

    Franz J. Hock

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer-Verlag Berlin Heidelberg

About this entry

Cite this entry

Boucher, P., Vogel, H.G. (2015). Inhibition of Cholesterol Biosynthesis. In: Hock, F. (eds) Drug Discovery and Evaluation: Pharmacological Assays. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-27728-3_48-1

Download citation

  • DOI: https://doi.org/10.1007/978-3-642-27728-3_48-1

  • Received:

  • Accepted:

  • Published:

  • Publisher Name: Springer, Berlin, Heidelberg

  • Online ISBN: 978-3-642-27728-3

  • eBook Packages: Springer Reference Biomedicine and Life SciencesReference Module Biomedical and Life Sciences

Publish with us

Policies and ethics

Search

Navigation