Advertisement

Microbial Statins

  • Leandro F. dos Santos
  • Júlio C. de CarvalhoEmail author
  • Rosália Rubel
  • Carlos Ricardo Soccol
Chapter

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.

References

  1. 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 2:44–46CrossRefGoogle Scholar
  2. Arikan S, Bahceci M, Tuzcu A et al (2012) Postprandial hyperlipidemia in overt and subclinical hypothyroidism. Eur J Intern Med 12(6):e141–e145CrossRefGoogle Scholar
  3. 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 11:1527–1531CrossRefGoogle Scholar
  4. Barrios-gonzález J, Miranda RU (2010) Biotechnological production and applications of statins. Appl Microbiol Biotechnol 85:869–883CrossRefGoogle Scholar
  5. Benedetti A, Manzoni M, Nichele M, Rollini M (2002) Process for the production of pravastatin and lovastatin. EP1266967.Google Scholar
  6. Berger C, Xia F, Maurer MH, Schwab S (2008) Neuroprotection by pravastatin in acute ischemic stroke in rats. Brain Res Rev 58:48–56CrossRefGoogle Scholar
  7. Betteridge J (2010) Pitavastatin – results from phase III & IV. Atheroscler Suppl 11:8–14CrossRefGoogle Scholar
  8. Bizukojc M, Pawlowska B, Ledakowicz S (2007) Supplementation of the cultivation media with B-group vitamins enhances lovastatin biosynthesis by Aspergillus terreus. J Biotechnol 127:258–268CrossRefGoogle Scholar
  9. Bobek P, Galbavy S (1999) Hypocholesterolemic and antiatherogenic effect of oyster mushroom (Pleurotus ostreatus) in rabbits. Nahrung/Food 43:339–342CrossRefGoogle Scholar
  10. Borshch VN, Andreeva ER, Kuz’min SG, Vozovikov IN (2012) New medicines and approaches to treatment of atherosclerosis. Russ J Gen Chem 82:554–563CrossRefGoogle Scholar
  11. 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 161:83–88CrossRefGoogle Scholar
  12. Brown MS, Goldstein JL (2004) A tribute to Akira Endo, discoverer of a “Penicillin” for cholesterol. Atheroscler Suppl 5:13–16CrossRefGoogle Scholar
  13. Brull DJ, Sanders J, Rumley A et al (2001) Statin therapy and the acute inflammatory response after coronary artery bypass grafting. Am J Cardiol 88:431–433CrossRefGoogle Scholar
  14. Campo VL, Carvalho I (2007) Estatinas hipolipidêmicas e novas tendências terapêuticas. Química Nova 30:425–430CrossRefGoogle Scholar
  15. 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 142:203–217CrossRefGoogle Scholar
  16. 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 33:270–277CrossRefGoogle Scholar
  17. 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 123:176–181CrossRefGoogle Scholar
  18. Catapano AL (2010) Pitavastatin – pharmacological profile from early phase studies. Atheroscler Suppl 11:3–7CrossRefGoogle Scholar
  19. Chapman MJ, Redfern JS, McGovern ME, Giral P (2010) Niacin and fibrates in atherogenic dyslipidemia: pharmacotherapy to reduce cardiovascular risk. Pharmacol Ther 126:314–345CrossRefGoogle Scholar
  20. 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 48:692–698CrossRefGoogle Scholar
  21. Darwish IA, Obaid ARM, Malaq HA (2009) New highly sensitive enzyme immunoassay for the determination of pravastatin in human plasma. Talanta 79:1478–1483CrossRefGoogle Scholar
  22. Ellis JT, Kilpatrick DL, Consigny P et al (2010) Therapy considerations in drug-eluting stents. Crit Rev Ther Drug Carrier Syst 22:1–25CrossRefGoogle Scholar
  23. Fehr T, Kahlert C, Fierz W et al (2004) Statin-induced immunomodulatory effects on human T cells in vivo. Atherosclerosis 175:83–90CrossRefGoogle Scholar
  24. Findlay S, Gunawardena D, Newsome-Stewart K, Skinner G (2007) The statin drugs. Consum Rep Best Buy Drugs. October 2005 to December 2006Google Scholar
  25. 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–e18CrossRefGoogle Scholar
  26. Gajendragadkar PR, Cooper DG, Walsh SR et al (2009) Novel uses for statins in surgical patients. Int J Surg (London) 7:285–290CrossRefGoogle Scholar
  27. Gu H, Tang C, Yang Y (2012) Psychological stress, immune response, and atherosclerosis. Atherosclerosis 223:69–77CrossRefGoogle Scholar
  28. 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 WO2003027302Google Scholar
  29. Haytko PN, Wildman AS (1992) Process for purification of HMG-CoA reductase inhibitors. WIPO WO/1992/016276Google Scholar
  30. 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 5:2261–2266Google Scholar
  31. 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 60:2014–2025Google Scholar
  32. Johannes BA, Mattheus PR, Piotr W (2009) Pravastatin extraction. WIPE WO 09728835Google Scholar
  33. 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 92:152–160CrossRefGoogle Scholar
  34. 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 1020110044613Google Scholar
  35. Klaassen P, Vollebregt AWH, Van den Berg MA, Meijrink B (2009) Improved statin production. United States Patent Application 20110223640Google Scholar
  36. Knopp RH (1999) Drug treatment of lipid disorders. N Engl J Med 12:498–511Google Scholar
  37. Koga J, Aikawa M (2012) Crosstalk between macrophages and smooth muscle cells in atherosclerotic vascular diseases. Vascul Pharmacol 57:24–28CrossRefGoogle Scholar
  38. 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 26:84–87CrossRefGoogle Scholar
  39. Koh KK, Son JW, Ahn JY et al (2004) Vascular effects of diet and statin in hypercholesterolemic patients. Int J Cardiol 95:185–191CrossRefGoogle Scholar
  40. 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 42:407–412CrossRefGoogle Scholar
  41. Kumar A, Kaur H, Devi P, Mohan V (2009) Role of coenzyme Q10 (CoQ10) in cardiac disease, hypertension and Meniere-like syndrome. Pharmacol Ther 124:259–268CrossRefGoogle Scholar
  42. Kumar MS, Jana SK, Senthil V et al (2000) Repeated fed-batch process for improving lovastatin production. Process Biochem 36:363–368CrossRefGoogle Scholar
  43. 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 49:898–902CrossRefGoogle Scholar
  44. Kumar Y, Thaper RK, Misra S et al (1998) Process for manufacturing simvastatin from lovastatin or mevinolinic acid. United States Patent 5763646Google Scholar
  45. Kzhyshkowska J, Neyen C, Gordon S (2012) Role of macrophage scavenger receptors in atherosclerosis. Immunobiology 217:492–502CrossRefGoogle Scholar
  46. Li JJ (2009) Triumph of the heart: the story of statins. Oxford University Press, New YorkGoogle Scholar
  47. Lisec B, Radež I, Žilnik LF (2012) Solvent extraction of lovastatin from a fermentation broth. Sep Purif Technol 96:187–193CrossRefGoogle Scholar
  48. Messner B, Bernhard D (2010) Cadmium and cardiovascular diseases: cell biology, pathophysiology, and epidemiological relevance. Biometals 23:811–822CrossRefGoogle Scholar
  49. Minquan M, Xiaoming J, Xiaoliang G et al (2006) The microorganism and the process for preparation of pravastatin. WIPE 04738297Google Scholar
  50. Miyake T, Uchitomi K, Zhang MY et al (2006) Effects of the principal nutrients on lovastatin production by Monascus pilosus. Biosci Biotechnol Biochem 70:1154–1159CrossRefGoogle Scholar
  51. 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 9:178–183CrossRefGoogle Scholar
  52. Murphree R (2008) Pfizer ads come clean about lipitor, but is anyone paying attention? TAC Integr Healthcare 3:45–46Google Scholar
  53. Nirogi R, Mudigonda K, Kandikere V (2007) Chromatography-mass spectrometry methods for the quantitation of statins in biological samples. J Pharm Biomed Anal 44:379–387CrossRefGoogle Scholar
  54. Nobunari S, Shunshi K, Mutsuo S et al (2003) Method of purifying pravastatin. European Patent Office WO2001JP09045Google Scholar
  55. 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 109:1247–1253CrossRefGoogle Scholar
  56. 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 5:698–703Google Scholar
  57. 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 79:820–825CrossRefGoogle Scholar
  58. Pater RM, Wnukowski P (2012) Crystalline form of pravastatine and process for the preparation thereof. WIPW WO/2012/085191Google Scholar
  59. Peng Y, Demain AL (2000) Bioconversion of compactin to pravastatin by Actinomadura sp. ATCC 55678. J Mol Catal B: Enzym 10:151–156CrossRefGoogle Scholar
  60. Porcel EMR, López JLC, Pérez JAS, Christ Y (2008) Lovastatin production by Aspergillus. J Chem Technol Biotechnol 83:1236–1243CrossRefGoogle Scholar
  61. 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 28:1247–1252CrossRefGoogle Scholar
  62. Rozman D, Monostory K (2010) Perspectives of the non-statin hypolipidemic agents. Pharmacol Ther 127:19–40CrossRefGoogle Scholar
  63. Saha SA, Arora RR (2011) Hyperlipidaemia and cardiovascular disease: do fibrates have a role? Curr Opin Lipidol 22:270–276CrossRefGoogle Scholar
  64. Sakaki T (2012) Practical application of cytochrome P450. Biol Pharm Bull 35:844–849CrossRefGoogle Scholar
  65. Samiee SM, Moazamil N, Haghighi S et al (2003) Screening of lovastatin production by filamentous fungi. Iran Biomed J 7:29–33Google Scholar
  66. 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):201–208Google Scholar
  67. 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 73:1054–1058CrossRefGoogle Scholar
  68. Schneider I, Kressel G, Meyer A et al (2011) Lipid lowering effects of oyster mushroom (Pleurotus ostreatus) in humans. J Funct Foods 3:17–24CrossRefGoogle Scholar
  69. Seenivas A, Subhagar S, Aravindan R, Viruthagiri T (2008) Microbial production and biomedical applications of lovastatin. Indian J Pharm Sci 70:701–709CrossRefGoogle Scholar
  70. Seraman S, Rajendran A, Thangavelu V (2010) Statistical optimization of anticholesterolemic drug lovastatin production by the red mold Monascus purpureus. Food Bioproducts Process 88:266–276CrossRefGoogle Scholar
  71. Serizawa N (1996) Biochemical and molecular approaches for production of pravastatin, a potent cholesterol-lowering drug. Biotechnol Annu Rev 2:373–389CrossRefGoogle Scholar
  72. Sorrentino F, Roy I, Keshavarz T (2010) Impact of linoleic acid supplementation on lovastatin production in Aspergillus terreus cultures. Appl Microbiol Biotechnol 88:65–73CrossRefGoogle Scholar
  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 5:231–240Google Scholar
  74. Steinbrecher UP (1999) Receptors for oxidized low density lipoprotein. Biochim Biophys Acta 1436:279–298CrossRefGoogle Scholar
  75. Straathof AJJ (2011) The proportion of downstream costs in fermentative production processes. Compr Biotechnol 2:811–814CrossRefGoogle Scholar
  76. Strey CH, Young JM, Molyneux SL et al (2005) Endothelium-ameliorating effects of statin therapy and coenzyme Q10 reductions in chronic heart failure. Atherosclerosis 179:201–206CrossRefGoogle Scholar
  77. 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 9:303–310CrossRefGoogle Scholar
  78. Subramanian S, Chait A (2012) Hypertriglyceridemia secondary to obesity and diabetes. Biochim Biophys Acta 1821:819–825CrossRefGoogle Scholar
  79. Szakács G, Morovján G, Tegendry RP (1998) Production of lovastatin by a wild strain of Aspergillus terreus. Biotechnol Lett 20:411–415CrossRefGoogle Scholar
  80. Talayero BG, Sacks FM (2011) The role of triglycerides in atherosclerosis. Curr Cardiol Rep 13:544–552CrossRefGoogle Scholar
  81. 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 73:1–15CrossRefGoogle Scholar
  82. 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 12:184Google Scholar
  83. Vaid S, Narula P (2006) Process for preparing simvastatin from lovastatin amine salts in three steps. WIPO Patent Application WO/2006/072963Google Scholar
  84. Valera HR, Gomes J, Lakshmi S et al (2005) Lovastatin production by solid state fermentation using Aspergillus flavipes. Enzyme Microb Technol 37:521–526CrossRefGoogle Scholar
  85. 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 21:123–125CrossRefGoogle Scholar
  86. Wagner M, Zollner G, Trauner M (2009) New molecular insights into the mechanisms of cholestasis. J Hepatol 51:565–580CrossRefGoogle Scholar
  87. 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 163:81–85CrossRefGoogle Scholar
  88. 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 210:109–116CrossRefGoogle Scholar
  89. Weber MS, Steinman L, Zamvil SS (2007) Statins-treatment option for central nervous system autoimmune disease? Neurotherapeutics 4:693–700CrossRefGoogle Scholar
  90. Wexler BC (1971) Comparative aspects of hyperadrenocorticism and arteriosclerosis. Hum Pathol 2:180–181CrossRefGoogle Scholar
  91. 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 7:907–912CrossRefGoogle Scholar
  92. Winkelnkemper T, Schuldt S, Schembecker G (2011) Systematic downstream process development for purification of baccatin III with key performance indicators. Sep Purif Technol 77:355–366CrossRefGoogle Scholar
  93. 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 82:1663–1672CrossRefGoogle Scholar
  94. Østerud B, Bjørklid E (2003) Role of monocytes in atherogenesis. Physiol Rev 83:1069–1112Google Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Leandro F. dos Santos
    • 1
  • Júlio C. de Carvalho
    • 1
    Email author
  • Rosália Rubel
    • 1
  • Carlos Ricardo Soccol
    • 1
  1. 1.Department of Biotechnology and Bioprocess EngineeringACF Centro Politécnico, Federal University of Paraná – UFPRCuritibaBrazil

Personalised recommendations