Abstract
Statins are a class of antihypercholesterolemic (or cholesterol-lowering) drugs which act on the liver by reducing steroid biosynthesis by inhibiting the activity of HMG-CoA reductase, the enzyme responsible for the first step in the synthesis of cholesterol (and other biomolecules). This, in turn, causes the reduction of the concentration of LDL (low-density lipoproteins) associated with increased risk of coronary disease, stroke, and heart attack. The market for statins is around 25–30 billion dollars, with synthetic compounds such as atorvastatin having a large market share. However, microbial statins, such as lovastatin and pravastatin, have a market share around 10 %, while the semisynthetic simvastatin has a 50 % market. Extracts from Aspergillus terreus and Nocardia autotrophica, as well as raw biomass rich in statins from oyster mushroom or Monascus sp., are also sources of natural statins. This chapter describes briefly the action of statins, the market for these drugs, the potential for new microbial statins, and the production process for lovastatin and pravastatin.
Keywords
- Cholesteryl Ester Transfer Protein
- Aspergillus Terreus
- Cholesteryl Ester Transfer Protein Inhibition
- Lovastatin Production
- Increase Blood Concentration
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
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Ahmad A, Panda BP, Mujeeb M (2010) Screening of nutrient parameters for mevastatin production by Penicillium citrinum MTCC 1256 under submerged fermentation using the Plackett-Burman design. J Pharm Bioallied Sci 2:44–46
Arikan S, Bahceci M, Tuzcu A et al (2012) Postprandial hyperlipidemia in overt and subclinical hypothyroidism. Eur J Intern Med 12(6):e141–e145
Auclair K, Kennedy J, Richard C, Vederas JC (2001) Conversion of cyclic nonaketides to lovastatin and compactin by a lovC deficient mutant of Aspergillus terreus. Bioorg Med Chem Lett 11:1527–1531
Barrios-gonzález J, Miranda RU (2010) Biotechnological production and applications of statins. Appl Microbiol Biotechnol 85:869–883
Benedetti A, Manzoni M, Nichele M, Rollini M (2002) Process for the production of pravastatin and lovastatin. EP1266967.
Berger C, Xia F, Maurer MH, Schwab S (2008) Neuroprotection by pravastatin in acute ischemic stroke in rats. Brain Res Rev 58:48–56
Betteridge J (2010) Pitavastatin – results from phase III & IV. Atheroscler Suppl 11:8–14
Bizukojc M, Pawlowska B, Ledakowicz S (2007) Supplementation of the cultivation media with B-group vitamins enhances lovastatin biosynthesis by Aspergillus terreus. J Biotechnol 127:258–268
Bobek P, Galbavy S (1999) Hypocholesterolemic and antiatherogenic effect of oyster mushroom (Pleurotus ostreatus) in rabbits. Nahrung/Food 43:339–342
Borshch VN, Andreeva ER, Kuz’min SG, Vozovikov IN (2012) New medicines and approaches to treatment of atherosclerosis. Russ J Gen Chem 82:554–563
Bouraoui L, Cruz-Garcia L, Gutiérrez J et al (2012) Regulation of lipoprotein lipase gene expression by insulin and troglitazone in rainbow trout (Oncorhynchus mykiss) adipocyte cells in culture. Comp Biochem Physiol 161:83–88
Brown MS, Goldstein JL (2004) A tribute to Akira Endo, discoverer of a “Penicillin” for cholesterol. Atheroscler Suppl 5:13–16
Brull DJ, Sanders J, Rumley A et al (2001) Statin therapy and the acute inflammatory response after coronary artery bypass grafting. Am J Cardiol 88:431–433
Campo VL, Carvalho I (2007) Estatinas hipolipidêmicas e novas tendências terapêuticas. Química Nova 30:425–430
Cantagrel V, Lefeber DJ, Ng BG et al (2010) SRD5A3 is required for converting polyprenol to dolichol and is mutated in a congenital glycosylation disorder. Cell 142:203–217
Casas López J, Sánchez Pérez J, Fernández Sevilla J et al (2003) Production of lovastatin by Aspergillus terreus: effects of the C:N ratio and the principal nutrients on growth and metabolite production. Enzyme Microb Technol 33:270–277
Casey RG, Joyce M, Roche-Nagle G et al (2005) Pravastatin modulates early diabetic nephropathy in an experimental model of diabetic renal disease. J Surg Res 123:176–181
Catapano AL (2010) Pitavastatin – pharmacological profile from early phase studies. Atheroscler Suppl 11:3–7
Chapman MJ, Redfern JS, McGovern ME, Giral P (2010) Niacin and fibrates in atherogenic dyslipidemia: pharmacotherapy to reduce cardiovascular risk. Pharmacol Ther 126:314–345
Chen G, Luo Y-C, Ji B-P et al (2011) Hypocholesterolemic effects of Auricularia auricula ethanol extract in ICR mice fed a cholesterol-enriched diet. J Food Sci Technol 48:692–698
Darwish IA, Obaid ARM, Malaq HA (2009) New highly sensitive enzyme immunoassay for the determination of pravastatin in human plasma. Talanta 79:1478–1483
Ellis JT, Kilpatrick DL, Consigny P et al (2010) Therapy considerations in drug-eluting stents. Crit Rev Ther Drug Carrier Syst 22:1–25
Fehr T, Kahlert C, Fierz W et al (2004) Statin-induced immunomodulatory effects on human T cells in vivo. Atherosclerosis 175:83–90
Findlay S, Gunawardena D, Newsome-Stewart K, Skinner G (2007) The statin drugs. Consum Rep Best Buy Drugs. October 2005 to December 2006
Fukui M, Tanaka M, Toda H et al (2011) Risk factors for development of diabetes mellitus, hypertension and dyslipidemia. Diabetes Res Clin Pract 94:e15–e18
Gajendragadkar PR, Cooper DG, Walsh SR et al (2009) Novel uses for statins in surgical patients. Int J Surg (London) 7:285–290
Gu H, Tang C, Yang Y (2012) Psychological stress, immune response, and atherosclerosis. Atherosclerosis 223:69–77
Gururaja R, Goel A, Sridharan M et al (2003) Producing pravastatin sodium salt for use as antihyper-cholesterolemic agent, by fermentation under optimal fermentation parameters using new strain of Streptomyces flavovirens. WIPO WO2003027302
Haytko PN, Wildman AS (1992) Process for purification of HMG-CoA reductase inhibitors. WIPO WO/1992/016276
Hor SY, Farsi E, Yam MF et al (2011) Lipid-lowering effects of Coriolus versicolor extract in poloxamer 407-induced hypercholesterolaemic rats and high cholesterol-fed rats. J Med Plants Res 5:2261–2266
Jia Z, Zhang X, Zhao Y, Cao X (2010) Enhancement of lovastatin production by supplementing polyketide antibiotics to the submerged culture of Aspergillus terreus. Biotechnol Appl Biochem 60:2014–2025
Johannes BA, Mattheus PR, Piotr W (2009) Pravastatin extraction. WIPE WO 09728835
Jones PH, Davidson MH, Stein EA et al (2003) Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR Trial). Am J Cardiol 92:152–160
Kim JS, Youk YM, Ko HS, Kang DH (2011) PCR primer for detecting lovastatin-producing strain and a detection method using the same. Korean Patent Abstracts 1020110044613
Klaassen P, Vollebregt AWH, Van den Berg MA, Meijrink B (2009) Improved statin production. United States Patent Application 20110223640
Knopp RH (1999) Drug treatment of lipid disorders. N Engl J Med 12:498–511
Koga J, Aikawa M (2012) Crosstalk between macrophages and smooth muscle cells in atherosclerotic vascular diseases. Vascul Pharmacol 57:24–28
Koh J-H, Kim J-M, Chang U-J, Suh H-J (2003) Hypocholesterolemic effect of hot-water extract from mycelia of Cordyceps sinensis. Biol Pharm Bull 26:84–87
Koh KK, Son JW, Ahn JY et al (2004) Vascular effects of diet and statin in hypercholesterolemic patients. Int J Cardiol 95:185–191
Komagata D, Shimada H, Murakawa S, Endo A (1989) Biosynthesis of monacolins: conversion of monacolin L to monacolin J by a monooxygenase of Monascus ruber. J Antibiot 42:407–412
Kumar A, Kaur H, Devi P, Mohan V (2009) Role of coenzyme Q10 (CoQ10) in cardiac disease, hypertension and Meniere-like syndrome. Pharmacol Ther 124:259–268
Kumar MS, Jana SK, Senthil V et al (2000) Repeated fed-batch process for improving lovastatin production. Process Biochem 36:363–368
Kumar S, Srivastava N, Gomes J (2011) The effect of lovastatin on oxidative stress and antioxidant enzymes in hydrogen peroxide intoxicated rat. Food Chem Toxicol 49:898–902
Kumar Y, Thaper RK, Misra S et al (1998) Process for manufacturing simvastatin from lovastatin or mevinolinic acid. United States Patent 5763646
Kzhyshkowska J, Neyen C, Gordon S (2012) Role of macrophage scavenger receptors in atherosclerosis. Immunobiology 217:492–502
Li JJ (2009) Triumph of the heart: the story of statins. Oxford University Press, New York
Lisec B, Radež I, Žilnik LF (2012) Solvent extraction of lovastatin from a fermentation broth. Sep Purif Technol 96:187–193
Messner B, Bernhard D (2010) Cadmium and cardiovascular diseases: cell biology, pathophysiology, and epidemiological relevance. Biometals 23:811–822
Minquan M, Xiaoming J, Xiaoliang G et al (2006) The microorganism and the process for preparation of pravastatin. WIPE 04738297
Miyake T, Uchitomi K, Zhang MY et al (2006) Effects of the principal nutrients on lovastatin production by Monascus pilosus. Biosci Biotechnol Biochem 70:1154–1159
Morikawa S, Takabe W, Mataki C et al (2002) The effect of statins on mRNA levels of genes related to inflammation, coagulation, and vascular constriction in HUVEC. J Ateroscler Thromb 9:178–183
Murphree R (2008) Pfizer ads come clean about lipitor, but is anyone paying attention? TAC Integr Healthcare 3:45–46
Nirogi R, Mudigonda K, Kandikere V (2007) Chromatography-mass spectrometry methods for the quantitation of statins in biological samples. J Pharm Biomed Anal 44:379–387
Nobunari S, Shunshi K, Mutsuo S et al (2003) Method of purifying pravastatin. European Patent Office WO2001JP09045
Nozue T, Yamamoto S, Tohyama S et al (2012) Comparison of arterial remodeling and changes in plaque composition between patients with progression versus regression of coronary atherosclerosis during statin therapy (from the TRUTH study). Am J Cardiol 109:1247–1253
Osman M, Khattab O, Zaghlol G, Abd El-Hameed R (2011) Screening for the production of cholesterol lowering drugs (lovastatin) by some fungi. Aust J Basic Appl Sci 5:698–703
Ottosson M, Vikman-Adolfsson K, Enerbäck S et al (1994) The effects of cortisol on the regulation of lipoprotein lipase activity in human adipose tissue. J Clin Endocrinol Metab 79:820–825
Pater RM, Wnukowski P (2012) Crystalline form of pravastatine and process for the preparation thereof. WIPW WO/2012/085191
Peng Y, Demain AL (2000) Bioconversion of compactin to pravastatin by Actinomadura sp. ATCC 55678. J Mol Catal B: Enzym 10:151–156
Porcel EMR, López JLC, Pérez JAS, Christ Y (2008) Lovastatin production by Aspergillus. J Chem Technol Biotechnol 83:1236–1243
Riphagen IJ, van der Veer E, Muskiet FAJ, DeJongste MJL (2012) Myopathy during statin therapy in the daily practice of an outpatient cardiology clinic: prevalence, predictors and relation with vitamin D. Curr Med Res Opin 28:1247–1252
Rozman D, Monostory K (2010) Perspectives of the non-statin hypolipidemic agents. Pharmacol Ther 127:19–40
Saha SA, Arora RR (2011) Hyperlipidaemia and cardiovascular disease: do fibrates have a role? Curr Opin Lipidol 22:270–276
Sakaki T (2012) Practical application of cytochrome P450. Biol Pharm Bull 35:844–849
Samiee SM, Moazamil N, Haghighi S et al (2003) Screening of lovastatin production by filamentous fungi. Iran Biomed J 7:29–33
Santos LF, Zanatta AL, Soccol VT, Torres MF, Bonatto SJR, Rubel R, Soccol CR (2012) Hypolipidemic and antiatherosclerotic potential of Pleurotus ostreatus, cultived by submerged fermentation in the high-fat diet fed rats. Biotechnol Bioproc Eng 18(1):201–208
Sayyad SA, Panda BP, Javed S, Ali M (2007) Optimization of nutrient parameters for lovastatin production by Monascus purpureus MTCC 369 under submerged fermentation using response surface methodology. Appl Microbiol Biotechnol 73:1054–1058
Schneider I, Kressel G, Meyer A et al (2011) Lipid lowering effects of oyster mushroom (Pleurotus ostreatus) in humans. J Funct Foods 3:17–24
Seenivas A, Subhagar S, Aravindan R, Viruthagiri T (2008) Microbial production and biomedical applications of lovastatin. Indian J Pharm Sci 70:701–709
Seraman S, Rajendran A, Thangavelu V (2010) Statistical optimization of anticholesterolemic drug lovastatin production by the red mold Monascus purpureus. Food Bioproducts Process 88:266–276
Serizawa N (1996) Biochemical and molecular approaches for production of pravastatin, a potent cholesterol-lowering drug. Biotechnol Annu Rev 2:373–389
Sorrentino F, Roy I, Keshavarz T (2010) Impact of linoleic acid supplementation on lovastatin production in Aspergillus terreus cultures. Appl Microbiol Biotechnol 88:65–73
Sripalakit P, Riunkesorn J, Saraphanchotiwitthaya A (2011) Utilisation of vegetable oils in the production of lovastatin by Aspergillus terreus ATCC 20542 in submerged cultivation. Maejo Int J Sci Technol 5:231–240
Steinbrecher UP (1999) Receptors for oxidized low density lipoprotein. Biochim Biophys Acta 1436:279–298
Straathof AJJ (2011) The proportion of downstream costs in fermentative production processes. Compr Biotechnol 2:811–814
Strey CH, Young JM, Molyneux SL et al (2005) Endothelium-ameliorating effects of statin therapy and coenzyme Q10 reductions in chronic heart failure. Atherosclerosis 179:201–206
Subhagar S, Aravindan R, Viruthagiri T (2009) Response surface optimization of mixed substrate solid state fermentation for the production of lovastatin by Monascus purpureus. Eng Life Sci 9:303–310
Subramanian S, Chait A (2012) Hypertriglyceridemia secondary to obesity and diabetes. Biochim Biophys Acta 1821:819–825
Szakács G, Morovján G, Tegendry RP (1998) Production of lovastatin by a wild strain of Aspergillus terreus. Biotechnol Lett 20:411–415
Talayero BG, Sacks FM (2011) The role of triglycerides in atherosclerosis. Curr Cardiol Rep 13:544–552
Teramoto T, Kashiwagi A, Ishibashi S et al (2012) Cross-sectional survey to assess the status of lipid management in high-risk patients with dyslipidemia: clinical impact of combination therapy with Ezetimibe. Ther Res Clin Exp 73:1–15
Tzotzas T, Karras S, Gautier T et al (2011) Exploring the contribution of plasma CETP to the modulation of HDL cholesterol during niacin administration in diabetic patients with dyslipidemia. Atherosclerosis Suppl 12:184
Vaid S, Narula P (2006) Process for preparing simvastatin from lovastatin amine salts in three steps. WIPO Patent Application WO/2006/072963
Valera HR, Gomes J, Lakshmi S et al (2005) Lovastatin production by solid state fermentation using Aspergillus flavipes. Enzyme Microb Technol 37:521–526
Vilches Ferrón MA, Casas López JL, Sánchez Pérez JA et al (2005) Rapid screening of Aspergillus terreus mutants for overproduction of lovastatin. World J Microbiol Biotechnol 21:123–125
Wagner M, Zollner G, Trauner M (2009) New molecular insights into the mechanisms of cholestasis. J Hepatol 51:565–580
Watanabe I, Nara F, Serizawa N (1995) Cloning, characterization and expression of the gene encoding cytochrome P-450sca-2 from Streptomyces carbophilus involved in production of pravastatin, a specific HMG-CoA reductase inhibitor. Gene 163:81–85
Watanabe I, Serizawa N (1998) Molecular approaches for production of pravastatin, a HMG-CoA reductase inhibitor : transcriptional regulation of the cytochrome P450 gene from Streptomyces carbophilus sca by ML-236B sodium salt and phenobarbital. Gene 210:109–116
Weber MS, Steinman L, Zamvil SS (2007) Statins-treatment option for central nervous system autoimmune disease? Neurotherapeutics 4:693–700
Wexler BC (1971) Comparative aspects of hyperadrenocorticism and arteriosclerosis. Hum Pathol 2:180–181
Whigan DB, Ivashkiv E, Cohen AI (1989) Determination of pravastatin sodium and its isomeric metabolite in human urine by HPLC with UV detection. J Pharm Biomed Anal 7:907–912
Winkelnkemper T, Schuldt S, Schembecker G (2011) Systematic downstream process development for purification of baccatin III with key performance indicators. Sep Purif Technol 77:355–366
Zhong W-B, Hsu S-P, Ho P-Y et al (2011) Lovastatin inhibits proliferation of anaplastic thyroid cancer cells through up-regulation of p27 by interfering with the Rho/ROCK-mediated pathway. Biochem Pharmacol 82:1663–1672
Østerud B, Bjørklid E (2003) Role of monocytes in atherogenesis. Physiol Rev 83:1069–1112
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dos Santos, L.F., de Carvalho, J.C., Rubel, R., Soccol, C.R. (2014). Microbial Statins. In: Brar, S., Dhillon, G., Soccol, C. (eds) Biotransformation of Waste Biomass into High Value Biochemicals. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-8005-1_13
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