Therapeutic implication of coenzyme Q10 during statin therapy: pros and cons

Document Type : Review Article

Authors

1 Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences

2 Zanjan Applied Pharmacology Research Center, Zanjan University of Medical sciences

Abstract

Coenzyme Q10 (CoQ10) is a vitamin-like substance, and a natural intermediate of electron transport chain (ETC) of mitochondria which can accepts and donates electrons from complex I to complex II. CoQ10 shares a biosynthetic pathway with cholesterol, therefore it can be a potential target of the widely available lipid-lowering agents. The lipid lowering drugs such as statins, are widely administered to individuals who have high cholesterol levels and potential risk for cardiovascular diseases. Statins do not cause serious adverse effects in human however its long-term administration can cause a variety of myopatic complaints.This article reviews the a) clinical benefits of CoQ10 b) association between administration of statin and CoQ10 deficiency and c) involvement of CoQ10 in statin-associated myopathy. 

  1. Fulgencio JP, Kohl C, Girard J, Pegorier JP. Troglitazone inhibits fatty acid oxidation and esterification, and gluconeogenesis in isolated
  2. hepatocytes from starved rats. Diabetes. 1996;45(11):1556-62. Epub 1996/11/01. PubMed PMID: 8866561.
  3. Blumenthal RS. Statins: effective antiatherosclerotic therapy. Am Heart J. 2000;139(4):577-83. Epub 2000/03/31. doi: S0002-8703(00)90033-4 [pii]. PubMed PMID: 10740137.
  4. Hargreaves IP, Duncan AJ, Heales SJ, Land JM. The effect of HMG-CoA reductase inhibitors on coenzyme Q10: possible biochemical/clinical implications. Drug Saf. 2005;28(8):659-76. Epub 2005/07/29. doi: 2882 [pii]. PubMed PMID: 16048353.
  5. Grundy SM. HMG-CoA reductase inhibitors for treatment of hypercholesterolemia. N Engl J Med. 1988;319(1):24-33. Epub 1988/07/07. doi: 10.1056/NEJM198807073190105. PubMed PMID: 3288867.
  6. van Leuven SI, Kastelein JJ. Atorvastatin. Expert Opin Pharmacother. 2005;6(7):1191-203. Epub 2005/06/17. doi: 10.1517/14656566.6.7.1191. PubMed PMID: 15957972.
  7. Singh DK, Li L, Porter TD. Policosanol inhibits cholesterol synthesis in hepatoma cells by activation of AMP-kinase. J Pharmacol Exp Ther. 2006;318(3):1020-6. Epub 2006/05/23. doi: jpet.106.107144 [pii]
  8. 1124/jpet.106.107144. PubMed PMID: 16714400.
  9. Parker RA, Clark RW, Sit SY, Lanier TL, Grosso RA, Wright JJ. Selective inhibition of cholesterol synthesis in liver versus extrahepatic tissues by HMG-CoA reductase inhibitors. J Lipid Res. 1990;31(7):1271-82. Epub 1990/07/01. PubMed PMID: 2401858.
  10. Wasko BM, Smits JP, Shull LW, Wiemer DF, Hohl RJ. A novel bisphosphonate inhibitor of squalene synthase combined with a statin or a nitrogenous bisphosphonate in vitro. J Lipid Res. 2011;52(11):1957-64. Epub 2011/09/10. doi: jlr.M016089 [pii]
  11. 1194/jlr.M016089. PubMed PMID: 21903868.
  12. Gebhardt R. Amplification of palmitate-induced inhibition of cholesterol biosynthesis in cultured rat hepatocytes by garlic-derived organosulfur compounds. Phytomedicine. 1995;2(1):29-34. Epub 1995/07/01. doi: S0944-7113(11)80045-0 [pii]
  13. 1016/S0944-7113(11)80045-0. PubMed PMID: 23196097.
  14. Cho BH, Xu S. Effects of allyl mercaptan and various allium-derived compounds on cholesterol synthesis and secretion in Hep-G2 cells. Comp Biochem Physiol C Toxicol Pharmacol. 2000;126(2):195-201. Epub 2000/10/29. PubMed PMID: 11050691.
  15. Sun S, McKenna CE. Farnesyl pyrophosphate synthase modulators: a patent review (2006 - 2010). Expert Opin Ther Pat. 2011;21(9):1433-51. Epub 2011/06/28. doi: 10.1517/13543776.2011.593511. PubMed PMID: 21702715.
  16. Rogers MJ. New insights into the molecular mechanisms of action of bisphosphonates. Curr Pharm Des. 2003;9(32):2643-58. Epub 2003/10/08. PubMed PMID: 14529538.
  17. Rodan GA, Reszka AA. Bisphosphonate mechanism of action. Curr Mol Med. 2002;2(6):571-7. Epub 2002/09/24. PubMed PMID: 12243249.
  18. Renaud JF, Schmid A, Romey G, Nano JL, Lazdunski M. Mevinolin, an inhibitor of cholesterol biosynthesis, drastically depresses Ca2+ channel activity and uncouples excitation from contraction in cardiac cells in culture. Proc Natl Acad Sci U S A. 1986;83(20):8007-11. Epub 1986/10/01. PubMed PMID: 2429325.
  19. Hiyoshi H, Yanagimachi M, Ito M, Ohtsuka I, Yoshida I, Saeki T, et al. Effect of ER-27856, a novel squalene synthase inhibitor, on plasma cholesterol in rhesus monkeys: comparison with 3-hydroxy-3-methylglutaryl-coa reductase inhibitors. J Lipid Res. 2000;41(7):1136-44. Epub 2000/07/07. PubMed PMID: 10884296.
  20. Davidson MH, Geohas CT. Efficacy of over-the-counter nutritional supplements. Curr Atheroscler Rep. 2003;5(1):15-21. Epub 2003/02/04. PubMed PMID: 12562537.
  21. Folkers K, Langsjoen P, Willis R, Richardson P, Xia LJ, Ye CQ, et al. Lovastatin decreases coenzyme Q levels in humans. Proc Natl Acad Sci U S A. 1990;87(22):8931-4. Epub 1990/11/01. PubMed PMID: 2247468.
  22. Ghirlanda G, Oradei A, Manto A, Lippa S, Uccioli L, Caputo S, et al. Evidence of plasma CoQ10-lowering effect by HMG-CoA reductase inhibitors: a double-blind, placebo-controlled study. J Clin Pharmacol. 1993;33(3):226-9. Epub 1993/03/01. PubMed PMID: 8463436.
  23. Laaksonen R, Ojala JP, Tikkanen MJ, Himberg JJ. Serum ubiquinone concentrations after short- and long-term treatment with HMG-CoA reductase inhibitors. Eur J Clin Pharmacol. 1994;46(4):313-7. Epub 1994/01/01. PubMed PMID: 7957515.
  24. Singh U, Devaraj S, Jialal I. Coenzyme Q10 supplementation and heart failure. Nutr Rev. 2007;65(6 Pt 1):286-93. Epub 2007/07/04. PubMed PMID: 17605305.
  25. Crane FL, Hatefi Y, Lester RL, Widmer C. Isolation of a quinone from beef heart mitochondria. Biochim Biophys Acta. 1957;25(1):220-1. Epub 1957/07/01. PubMed PMID: 13445756.
  26. Tarasiuk J, Liwo A, Wojtkowiak S, Dzieduszycka M, Tempczyk A, Garnier-Suillerot A, et al. Molecular determinants of singlet oxygen binding by anthraquinones in relation to their redox cycling activity. Anticancer Drug Des. 1991;6(5):399-416. Epub 1991/11/01. PubMed PMID: 1764163.
  27. Crane FL. Biochemical functions of coenzyme Q10. J Am Coll Nutr. 2001;20(6):591-8. Epub 2002/01/05. PubMed PMID: 11771674.
  28. Villalba JM, Navarro F, Cordoba F, Serrano A, Arroyo A, Crane FL, et al. Coenzyme Q reductase from liver plasma membrane: purification and role in trans-plasma-membrane electron transport. Proc Natl Acad Sci U S A. 1995;92(11):4887-91. Epub 1995/05/23. PubMed PMID: 7761418.
  29. Turunen M, Olsson J, Dallner G. Metabolism and function of coenzyme Q. Biochim Biophys Acta. 2004;1660(1-2):171-99. Epub 2004/02/06. doi: S0005273603003717 [pii]. PubMed PMID: 14757233.
  30. Okamoto T, Fukui K, Nakamoto M, Kishi T, Okishio T, Yamagami T, et al. High-performance liquid chromatography of coenzyme Q-related compounds and its application to biological materials. J Chromatogr. 1985;342(1):35-46. Epub 1985/07/12. PubMed PMID: 4044758.
  31. Aberg F, Appelkvist EL, Dallner G, Ernster L. Distribution and redox state of ubiquinones in rat and human tissues. Arch Biochem Biophys. 1992;295(2):230-4. Epub 1992/06/01. PubMed PMID: 1586151.
  32. Yamashita S, Yamamoto Y. Simultaneous detection of ubiquinol and ubiquinone in human plasma as a marker of oxidative stress. Anal Biochem. 1997;250(1):66-73. Epub 1997/07/15. doi: S0003-2697(97)92187-4 [pii]
  33. 1006/abio.1997.2187. PubMed PMID: 9234900.
  34. Tran UC, Clarke CF. Endogenous synthesis of coenzyme Q in eukaryotes. Mitochondrion. 2007;7 Suppl:S62-71. Epub 2007/05/08. doi: S1567-7249(07)00064-5 [pii]
  35. 1016/j.mito.2007.03.007. PubMed PMID: 17482885.
  36. Kawamukai M. Biosynthesis and bioproduction of coenzyme Q10 by yeasts and other organisms. Biotechnol Appl Biochem. 2009;53(Pt 4):217-26. Epub 2009/06/18. doi: BA20090035 [pii]
  37. 1042/BA20090035. PubMed PMID: 19531029.
  38. Saiki R, Nagata A, Kainou T, Matsuda H, Kawamukai M. Characterization of solanesyl and decaprenyl diphosphate synthases in mice and humans. FEBS J. 2005;272(21):5606-22. Epub 2005/11/03. doi: EJB4956 [pii]
  39. 1111/j.1742-4658.2005.04956.x. PubMed PMID: 16262699.
  40. Gin P, Hsu AY, Rothman SC, Jonassen T, Lee PT, Tzagoloff A, et al. The Saccharomyces cerevisiae COQ6 gene encodes a mitochondrial flavin-dependent monooxygenase required for coenzyme Q biosynthesis. J Biol Chem. 2003;278(28):25308-16. Epub 2003/05/02. doi: 10.1074/jbc.M303234200
  41. M303234200 [pii]. PubMed PMID: 12721307.
  42. Ernster L, Dallner G. Biochemical, physiological and medical aspects of ubiquinone function. Biochim Biophys Acta. 1995;1271(1):195-204. Epub 1995/05/24. PubMed PMID: 7599208.
  43. Forsmark-Andree P, Lee CP, Dallner G, Ernster L. Lipid peroxidation and changes in the ubiquinone content and the respiratory chain enzymes of submitochondrial particles. Free Radic Biol Med. 1997;22(3):391-400. Epub 1997/01/01. doi: S0891-5849(96)00330-9 [pii]. PubMed PMID: 8981030.
  44. Mitchell P. The protonmotive Q cycle: a general formulation. FEBS Lett. 1975;59(2):137-9. Epub 1975/11/15. doi: 0014-5793(75)80359-0 [pii]. PubMed PMID: 1227927.
  45. Dallner G, Sindelar PJ. Regulation of ubiquinone metabolism. Free Radic Biol Med. 2000;29(3-4):285-94. Epub 2000/10/18. doi: S0891-5849(00)00307-5 [pii]. PubMed PMID: 11035257.
  46. Olson RE, Rudney H. Biosynthesis of ubiquinone. Vitam Horm. 1983;40:1-43. Epub 1983/01/01. PubMed PMID: 6369767.
  47. Ranganathan S, Nambudiri AM, Rudney H. The regulation of ubiquinone synthesis in fibroblasts: the effect of modulators of beta-hydroxy-beta-methylglutaryl-coenzyme A reductase activity. Arch Biochem Biophys. 1981;210(2):592-7. Epub 1981/09/01. PubMed PMID: 7305347.
  48. Farmer JA. Aggressive lipid therapy in the statin era. Prog Cardiovasc Dis. 1998;41(2):71-94. Epub 1998/10/28. doi: S0033-0620(98)80006-6 [pii]. PubMed PMID: 9790411.
  49. Marks D, Thorogood M, Neil HA, Humphries SE. A review on the diagnosis, natural history, and treatment of familial hypercholesterolaemia. Atherosclerosis. 2003;168(1):1-14. Epub 2003/05/07. doi: S0021915002003301 [pii]. PubMed PMID: 12732381.
  50. Desager JP, Horsmans Y. Clinical pharmacokinetics of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors. Clin Pharmacokinet. 1996;31(5):348-71. Epub 1996/11/01. doi: 10.2165/00003088-199631050-00003. PubMed PMID: 9118584.
  51. Lea AP, McTavish D. Atorvastatin. A review of its pharmacology and therapeutic potential in the management of hyperlipidaemias. Drugs. 1997;53(5):828-47. Epub 1997/05/01. PubMed PMID: 9129869.
  52. Plosker GL, Dunn CI, Figgitt DP. Cerivastatin: a review of its pharmacological properties and therapeutic efficacy in the management of hypercholesterolaemia. Drugs. 2000;60(5):1179-206. Epub 2000/12/29. PubMed PMID: 11129127.
  53. Nawarskas JJ. HMG-CoA reductase inhibitors and coenzyme Q10. Cardiol Rev. 2005;13(2):76-9. Epub 2005/02/12. doi: 01.crd.0000154790.42283.a1 [pii]
  54. 1097/01.crd.0000154790.42283.a1. PubMed PMID: 15705257.
  55. Bischoff KM, Rodwell VW. Biosynthesis and characterization of (S)-and (R)-3-hydroxy-3-methylglutaryl coenzyme A. Biochem Med Metab Biol. 1992;48(2):149-58. Epub 1992/10/01. PubMed PMID: 1419147.
  56. Corsini A, Maggi FM, Catapano AL. Pharmacology of competitive inhibitors of HMG-CoA reductase. Pharmacol Res. 1995;31(1):9-27. Epub 1995/01/01. doi: 1043-6618(95)80042-5 [pii]. PubMed PMID: 7784310.
  57. Istvan ES, Deisenhofer J. Structural mechanism for statin inhibition of HMG-CoA reductase. Science. 2001;292(5519):1160-4. Epub 2001/05/12. doi: 10.1126/science.1059344
  58. /5519/1160 [pii]. PubMed PMID: 11349148.
  59. Takahashi R, Fujii T, Inoue Y, Takahashi H, Akashi M, Nishida R, et al. [Liver arterial infusion chemotherapy with adjuvant trastuzumab for the simultaneous treatment of liver and breast cancer-a case report]. Gan To Kagaku Ryoho.39(11):1707-10. Epub 2012/11/16. PubMed PMID: 23152024.
  60. Hidaka T, Fujii K, Funahashi I, Fukutomi N, Hosoe K. Safety assessment of coenzyme Q10 (CoQ10). Biofactors. 2008;32(1-4):199-208. Epub 2008/12/20. PubMed PMID: 19096117.
  61. Delanty N, Dichter MA. Oxidative injury in the nervous system. Acta Neurol Scand. 1998;98(3):145-53. Epub 1998/10/24. PubMed PMID: 9786609.
  62. Shults CW. Therapeutic role of coenzyme Q(10) in Parkinson's disease. Pharmacol Ther. 2005;107(1):120-30. Epub 2005/06/21. doi: S0163-7258(05)00054-9 [pii]
  63. 1016/j.pharmthera.2005.02.002. PubMed PMID: 15963354.
  64. Hodgson JM, Watts GF, Playford DA, Burke V, Croft KD. Coenzyme Q10 improves blood pressure and glycaemic control: a controlled trial in subjects with type 2 diabetes. Eur J Clin Nutr. 2002;56(11):1137-42. Epub 2002/11/13. doi: 10.1038/sj.ejcn.1601464. PubMed PMID: 12428181.
  65. Playford DA, Watts GF, Croft KD, Burke V. Combined effect of coenzyme Q10 and fenofibrate on forearm microcirculatory function in type 2 diabetes. Atherosclerosis. 2003;168(1):169-79. Epub 2003/05/07. doi: S0021915002004173 [pii]. PubMed PMID: 12732401.
  66. Watts GF, Playford DA, Croft KD, Ward NC, Mori TA, Burke V. Coenzyme Q(10) improves endothelial dysfunction of the brachial artery in Type II diabetes mellitus. Diabetologia. 2002;45(3):420-6. Epub 2002/03/27. doi: 10.1007/s00125-001-0760-y. PubMed PMID: 11914748.
  67. Mancini A, Conte B, De Marinis L, Hallgass ME, Pozza D, Oradei A, et al. Coenzyme Q10 levels in human seminal fluid: diagnostic and clinical implications. Mol Aspects Med. 1994;15 Suppl:s249-55. Epub 1994/01/01. PubMed PMID: 7752837.
  68. Balercia G, Arnaldi G, Fazioli F, Serresi M, Alleva R, Mancini A, et al. Coenzyme Q10 levels in idiopathic and varicocele-associated asthenozoospermia. Andrologia. 2002;34(2):107-11. Epub 2002/04/23. doi: 485 [pii]. PubMed PMID: 11966577.
  69. Portakal O, Ozkaya O, Erden Inal M, Bozan B, Kosan M, Sayek I. Coenzyme Q10 concentrations and antioxidant status in tissues of breast cancer patients. Clin Biochem. 2000;33(4):279-84. Epub 2000/08/11. doi: S0009-9120(00)00067-9 [pii]. PubMed PMID: 10936586.
  70. Fouad AA, Al-Mulhim AS, Jresat I. Therapeutic effect of coenzyme Q10 against experimentally-induced hepatocellular carcinoma in rats. Environ Toxicol Pharmacol. 2013;35(1):100-8. Epub 2013/01/01. doi: S1382-6689(12)00199-8 [pii]
  71. 1016/j.etap.2012.11.016. PubMed PMID: 23274416.
  72. Hodges S, Hertz N, Lockwood K, Lister R. CoQ10: could it have a role in cancer management? Biofactors. 1999;9(2-4):365-70. Epub 1999/07/23. PubMed PMID: 10416054.
  73. Navas P, Fernandez-Ayala DM, Martin SF, Lopez-Lluch G, De Caboa R, Rodriguez-Aguilera JC, et al. Ceramide-dependent caspase 3 activation is prevented by coenzyme Q from plasma membrane in serum-deprived cells. Free Radic Res. 2002;36(4):369-74. Epub 2002/06/19. PubMed PMID: 12069099.
  74. Bernardi P, Colonna R, Costantini P, Eriksson O, Fontaine E, Ichas F, et al. The mitochondrial permeability transition. Biofactors. 1998;8(3-4):273-81. Epub 1999/01/23. PubMed PMID: 9914829.
  75. Xue SY, Hebert VY, Hayes DM, Robinson CN, Glover M, Dugas TR. Nucleoside reverse transcriptase inhibitors induce a mitophagy-associated endothelial cytotoxicity that is reversed by coenzyme Q10 cotreatment. Toxicol Sci. 2013;134(2):323-34. Epub 2013/05/04. doi: kft105 [pii]
  76. 1093/toxsci/kft105. PubMed PMID: 23640862.
  77. Victor VM, Rocha M, Sola E, Banuls C, Garcia-Malpartida K, Hernandez-Mijares A. Oxidative stress, endothelial dysfunction and atherosclerosis. Curr Pharm Des. 2009;15(26):2988-3002. Epub 2009/09/17. PubMed PMID: 19754375.
  78. Lund KC, Wallace KB. Direct, DNA pol-gamma-independent effects of nucleoside reverse transcriptase inhibitors on mitochondrial bioenergetics. Cardiovasc Toxicol. 2004;4(3):217-28. Epub 2004/10/08. doi: CT:4:3:217 [pii]. PubMed PMID: 15470270.
  79. da Silva Machado C, Mendonca LM, Venancio VP, Bianchi ML, Antunes LM. Coenzyme Q10 protects Pc12 cells from cisplatin-induced DNA damage and neurotoxicity. Neurotoxicology. 2013;36:10-6. Epub 2013/02/26. doi: S0161-813X(13)00024-7 [pii]
  80. 1016/j.neuro.2013.02.004. PubMed PMID: 23434506.
  81. Kantor ED, Ulrich CM, Owen RW, Schmezer P, Neuhouser ML, Lampe JW, et al. Specialty supplement use and biologic measures of oxidative stress and DNA damage. Cancer Epidemiol Biomarkers Prev. 2013;22(12):2312-22. Epub 2013/08/07. doi: 1055-9965.EPI-13-0470 [pii]
  82. 1158/1055-9965.EPI-13-0470. PubMed PMID: 23917455.
  83. Ernster L, Forsmark-Andree P. Ubiquinol: an endogenous antioxidant in aerobic organisms. Clin Investig. 1993;71(8 Suppl):S60-5. Epub 1993/01/01. PubMed PMID: 8241707.
  84. Alleva R, Tomasetti M, Bompadre S, Littarru GP. Oxidation of LDL and their subfractions: kinetic aspects and CoQ10 content. Mol Aspects Med. 1997;18 Suppl:S105-12. Epub 1997/01/01. PubMed PMID: 9266511.
  85. Constantinescu A, Maguire JJ, Packer L. Interactions between ubiquinones and vitamins in membranes and cells. Mol Aspects Med. 1994;15 Suppl:s57-65. Epub 1994/01/01. PubMed PMID: 7752845.
  86. Cornelius N, Byron C, Hargreaves I, Guerra PF, Furdek AK, Land J, et al. Secondary coenzyme Q10 deficiency and oxidative stress in cultured fibroblasts from patients with riboflavin responsive multiple Acyl-CoA dehydrogenation deficiency. Hum Mol Genet. 2013;22(19):3819-27. Epub 2013/06/04. doi: ddt232 [pii]
  87. 1093/hmg/ddt232. PubMed PMID: 23727839.
  88. Sanoobar M, Eghtesadi S, Azimi A, Khalili M, Jazayeri S, Reza Gohari M. Coenzyme Q10 supplementation reduces oxidative stress and increases antioxidant enzyme activity in patients with relapsing-remitting multiple sclerosis. Int J Neurosci. 2013;123(11):776-82. Epub 2013/05/11. doi: 10.3109/00207454.2013.801844. PubMed PMID: 23659338.
  89. Lee BJ, Tseng YF, Yen CH, Lin PT. Effects of coenzyme Q10 supplementation (300 mg/day) on antioxidation and anti-inflammation in coronary artery disease patients during statins therapy: a randomized, placebo-controlled trial. Nutr J. 2013;12(1):142. Epub 2013/11/07. doi: 1475-2891-12-142 [pii]
  90. 1186/1475-2891-12-142. PubMed PMID: 24192015.
  91. Quinzii CM, Tadesse S, Naini A, Hirano M. Effects of inhibiting CoQ10 biosynthesis with 4-nitrobenzoate in human fibroblasts. PLoS One. 2012;7(2):e30606. Epub 2012/02/24. doi: 10.1371/journal.pone.0030606
  92. PONE-D-11-20595 [pii]. PubMed PMID: 22359546.
  93. Miyake Y, Shouzu A, Nishikawa M, Yonemoto T, Shimizu H, Omoto S, et al. Effect of treatment with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on serum coenzyme Q10 in diabetic patients. Arzneimittelforschung. 1999;49(4):324-9. Epub 1999/05/25. doi: 10.1055/s-0031-1300422. PubMed PMID: 10337451.
  94. Mortensen SA, Leth A, Agner E, Rohde M. Dose-related decrease of serum coenzyme Q10 during treatment with HMG-CoA reductase inhibitors. Mol Aspects Med. 1997;18 Suppl:S137-44. Epub 1997/01/01. PubMed PMID: 9266515.
  95. Watts GF, Castelluccio C, Rice-Evans C, Taub NA, Baum H, Quinn PJ. Plasma coenzyme Q (ubiquinone) concentrations in patients treated with simvastatin. J Clin Pathol. 1993;46(11):1055-7. Epub 1993/11/01. PubMed PMID: 8254097.
  96. Bargossi AM, Grossi G, Fiorella PL, Gaddi A, Di Giulio R, Battino M. Exogenous CoQ10 supplementation prevents plasma ubiquinone reduction induced by HMG-CoA reductase inhibitors. Mol Aspects Med. 1994;15 Suppl:s187-93. Epub 1994/01/01. PubMed PMID: 7752830.
  97. Laaksonen R, Jokelainen K, Sahi T, Tikkanen MJ, Himberg JJ. Decreases in serum ubiquinone concentrations do not result in reduced levels in muscle tissue during short-term simvastatin treatment in humans. Clin Pharmacol Ther. 1995;57(1):62-6. Epub 1995/01/01. doi: 0009-9236(95)90266-X [pii]
  98. 1016/0009-9236(95)90266-X. PubMed PMID: 7828383.
  99. Rotig A, Appelkvist EL, Geromel V, Chretien D, Kadhom N, Edery P, et al. Quinone-responsive multiple respiratory-chain dysfunction due to widespread coenzyme Q10 deficiency. Lancet. 2000;356(9227):391-5. Epub 2000/09/06. doi: S0140-6736(00)02531-9 [pii]
  100. 1016/S0140-6736(00)02531-9. PubMed PMID: 10972372.
  101. Gempel K, Topaloglu H, Talim B, Schneiderat P, Schoser BG, Hans VH, et al. The myopathic form of coenzyme Q10 deficiency is caused by mutations in the electron-transferring-flavoprotein dehydrogenase (ETFDH) gene. Brain. 2007;130(Pt 8):2037-44. Epub 2007/04/07. doi: awm054 [pii]
  102. 1093/brain/awm054. PubMed PMID: 17412732.
  103. Young AJ, Johnson S, Steffens DC, Doraiswamy PM. Coenzyme Q10: a review of its promise as a neuroprotectant. CNS Spectr. 2007;12(1):62-8. Epub 2006/12/29. PubMed PMID: 17192765.
  104. Caso G, Kelly P, McNurlan MA, Lawson WE. Effect of coenzyme q10 on myopathic symptoms in patients treated with statins. Am J Cardiol. 2007;99(10):1409-12. Epub 2007/05/12. doi: S0002-9149(07)00255-X [pii]
  105. 1016/j.amjcard.2006.12.063. PubMed PMID: 17493470.
  106. Willis RA, Folkers K, Tucker JL, Ye CQ, Xia LJ, Tamagawa H. Lovastatin decreases coenzyme Q levels in rats. Proc Natl Acad Sci U S A. 1990;87(22):8928-30. Epub 1990/11/01. PubMed PMID: 2247467.
  107. Bleske BE, Willis RA, Anthony M, Casselberry N, Datwani M, Uhley VE, et al. The effect of pravastatin and atorvastatin on coenzyme Q10. Am Heart J. 2001;142(2):E2. Epub 2001/08/02. doi: S0002-8703(01)52810-0 [pii]
  108. 1067/mhj.2001.116762. PubMed PMID: 11479481.
  109. Lamperti C, Naini AB, Lucchini V, Prelle A, Bresolin N, Moggio M, et al. Muscle coenzyme Q10 level in statin-related myopathy. Arch Neurol. 2005;62(11):1709-12. Epub 2005/11/16. doi: 62/11/1709 [pii]
  110. 1001/archneur.62.11.1709. PubMed PMID: 16286544.
  111. Paiva H, Thelen KM, Van Coster R, Smet J, De Paepe B, Mattila KM, et al. High-dose statins and skeletal muscle metabolism in humans: a randomized, controlled trial. Clin Pharmacol Ther. 2005;78(1):60-8. Epub 2005/07/09. doi: S0009923605001359 [pii]
  112. 1016/j.clpt.2005.03.006. PubMed PMID: 16003294.
  113. Emmanuele V, Lopez LC, Berardo A, Naini A, Tadesse S, Wen B, et al. Heterogeneity of coenzyme Q10 deficiency: patient study and literature review. Arch Neurol. 2012;69(8):978-83. Epub 2012/04/12. doi: archneurol.2012.206 [pii]
  114. 1001/archneurol.2012.206. PubMed PMID: 22490322.
  115. Kerr DS. Review of clinical trials for mitochondrial disorders: 1997-2012. Neurotherapeutics. 2013;10(2):307-19. Epub 2013/01/31. doi: 10.1007/s13311-013-0176-7. PubMed PMID: 23361264.
  116. Siciliano G, Mancuso M, Tedeschi D, Manca ML, Renna MR, Lombardi V, et al. Coenzyme Q10, exercise lactate and CTG trinucleotide expansion in myotonic dystrophy. Brain Res Bull. 2001;56(3-4):405-10. Epub 2001/11/24. doi: S0361-9230(01)00653-0 [pii]. PubMed PMID: 11719279.
  117. Spurney CF, Rocha CT, Henricson E, Florence J, Mayhew J, Gorni K, et al. CINRG pilot trial of coenzyme Q10 in steroid-treated Duchenne muscular dystrophy. Muscle Nerve. 2011;44(2):174-8. Epub 2011/06/24. doi: 10.1002/mus.22047. PubMed PMID: 21698649.
  118. Roffe L, Schmidt K, Ernst E. Efficacy of coenzyme Q10 for improved tolerability of cancer treatments: a systematic review. J Clin Oncol. 2004;22(21):4418-24. Epub 2004/10/30. doi: 22/21/4418 [pii]
  119. 1200/JCO.2004.02.034. PubMed PMID: 15514384.
  120. Chai W, Cooney RV, Franke AA, Shvetsov YB, Caberto CP, Wilkens LR, et al. Plasma coenzyme Q10 levels and postmenopausal breast cancer risk: the multiethnic cohort study. Cancer Epidemiol Biomarkers Prev. 2010;19(9):2351-6. Epub 2010/07/30. doi: 1055-9965.EPI-10-0396 [pii]
  121. 1158/1055-9965.EPI-10-0396. PubMed PMID: 20668119.
  122. Hill GJ, Shriver BJ, Arnett DB. Examining intentions to use CoQ10 amongst breast cancer patients. Am J Health Behav. 2006;30(3):313-21. Epub 2006/05/23. doi: 10.5555/ajhb.2006.30.3.313. PubMed PMID: 16712445.
  123. Lesperance ML, Olivotto IA, Forde N, Zhao Y, Speers C, Foster H, et al. Mega-dose vitamins and minerals in the treatment of non-metastatic breast cancer: an historical cohort study. Breast Cancer Res Treat. 2002;76(2):137-43. Epub 2002/11/28. PubMed PMID: 12452451.
  124. Kumar A, Kaur H, Devi P, Mohan V. Role of coenzyme Q10 (CoQ10) in cardiac disease, hypertension and Meniere-like syndrome. Pharmacol Ther. 2009;124(3):259-68. Epub 2009/07/30. doi: S0163-7258(09)00142-9 [pii]
  125. 1016/j.pharmthera.2009.07.003. PubMed PMID: 19638284.
  126. Ho MJ, Bellusci A, Wright JM. Blood pressure lowering efficacy of coenzyme Q10 for primary hypertension. Cochrane Database Syst Rev. 2009(4):CD007435. Epub 2009/10/13. doi: 10.1002/14651858.CD007435.pub2. PubMed PMID: 19821418.
  127. Kizhakekuttu TJ, Widlansky ME. Natural antioxidants and hypertension: promise and challenges. Cardiovasc Ther. 2010;28(4):e20-32. Epub 2010/04/08. doi: CDR137 [pii]
  128. 1111/j.1755-5922.2010.00137.x. PubMed PMID: 20370791.
  129. Talevi R, Barbato V, Fiorentino I, Braun S, Longobardi S, Gualtieri R. Protective effects of in vitro treatment with zinc, d-aspartate and coenzyme q10 on human sperm motility, lipid peroxidation and DNA fragmentation. Reprod Biol Endocrinol. 2013;11(1):81. Epub 2013/08/21. doi: 1477-7827-11-81 [pii]
  130. 1186/1477-7827-11-81. PubMed PMID: 23958080.
  131. Sheweita SA, Tilmisany AM, Al-Sawaf H. Mechanisms of male infertility: role of antioxidants. Curr Drug Metab. 2005;6(5):495-501. Epub 2005/10/27. PubMed PMID: 16248841.
  132. Mora-Esteves C, Shin D. Nutrient supplementation: improving male fertility fourfold. Semin Reprod Med. 2013;31(4):293-300. Epub 2013/06/19. doi: 10.1055/s-0033-1345277. PubMed PMID: 23775385.
  133. Liu J, Wang LN. Mitochondrial enhancement for neurodegenerative movement disorders: a systematic review of trials involving creatine, coenzyme q10, idebenone and mitoquinone. CNS Drugs. 2014;28(1):63-8. Epub 2013/11/19. doi: 10.1007/s40263-013-0124-4. PubMed PMID: 24242074.
  134. Morris G, Anderson G, Berk M, Maes M. Coenzyme Q10 depletion in medical and neuropsychiatric disorders: potential repercussions and therapeutic implications. Mol Neurobiol.48(3):883-903. Epub 2013/06/14. doi: 10.1007/s12035-013-8477-8. PubMed PMID: 23761046.
  135. Jankovic J, Poewe W. Therapies in Parkinson's disease. Curr Opin Neurol. 2012;25(4):433-47. Epub 2012/06/14. doi: 10.1097/WCO.0b013e3283542fc2. PubMed PMID: 22691758.
  136. Orsucci D, Mancuso M, Ienco EC, LoGerfo A, Siciliano G. Targeting mitochondrial dysfunction and neurodegeneration by means of coenzyme Q10 and its analogues. Curr Med Chem. 2011;18(26):4053-64. Epub 2011/08/10. doi: BSP/CMC/E-Pub/2011/ 304 [pii]. PubMed PMID: 21824087.
  137. Henchcliffe C, Beal MF. Mitochondrial biology and oxidative stress in Parkinson disease pathogenesis. Nat Clin Pract Neurol. 2008;4(11):600-9. Epub 2008/11/04. doi: ncpneuro0924 [pii]
  138. 1038/ncpneuro0924. PubMed PMID: 18978800.
  139. Schon EA, DiMauro S, Hirano M, Gilkerson RW. Therapeutic prospects for mitochondrial disease. Trends Mol Med. 2010;16(6):268-76. Epub 2010/06/18. doi: S1471-4914(10)00058-4 [pii]
  140. 1016/j.molmed.2010.04.007. PubMed PMID: 20556877.
  141. Montero R, Pineda M, Aracil A, Vilaseca MA, Briones P, Sanchez-Alcazar JA, et al. Clinical, biochemical and molecular aspects of cerebellar ataxia and Coenzyme Q10 deficiency. Cerebellum. 2007;6(2):118-22. Epub 2007/05/19. doi: 778834874 [pii]
  142. 1080/14734220601021700. PubMed PMID: 17510911.
  143. Berbel-Garcia A, Barbera-Farre JR, Etessam JP, Salio AM, Cabello A, Gutierrez-Rivas E, et al. Coenzyme Q 10 improves lactic acidosis, strokelike episodes, and epilepsy in a patient with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes). Clin Neuropharmacol. 2004;27(4):187-91. Epub 2004/08/21. doi: 00002826-200407000-00008 [pii]. PubMed PMID: 15319706.
  144. Triolo L, Lippa S, Oradei A, De Sole P, Mori R. Serum coenzyme Q10 in uremic patients on chronic hemodialysis. Nephron. 1994;66(2):153-6. Epub 1994/01/01. PubMed PMID: 8139734.
  145. Peerapanyasut W, Thamprasert K, Wongmekiat O. Ubiquinol supplementation protects against renal ischemia and reperfusion injury in rats. Free Radic Res.48(2):180-9. Epub 2013/10/25. doi: 10.3109/10715762.2013.858148. PubMed PMID: 24151980.
  146. Turk S, Baki A, Solak Y, Kayrak M, Atalay H, Gaipov A, et al. Coenzyme Q10 supplementation and diastolic heart functions in hemodialysis patients: a randomized double-blind placebo-controlled trial. Hemodial Int. 2013;17(3):374-81. Epub 2013/01/31. doi: 10.1111/hdi.12022. PubMed PMID: 23360359.
  147. Quinzii CM, Hirano M. Coenzyme Q and mitochondrial disease. Dev Disabil Res Rev.16(2):183-8. Epub 2010/09/08. doi: 10.1002/ddrr.108. PubMed PMID: 20818733.
  148. Mancuso M, Orsucci D, Volpi L, Calsolaro V, Siciliano G. Coenzyme Q10 in neuromuscular and neurodegenerative disorders. Curr Drug Targets.11(1):111-21. Epub 2009/12/19. doi: CDT-ms41 [pii]. PubMed PMID: 20017723.
  149. Mestre T, Ferreira J, Coelho MM, Rosa M, Sampaio C. Therapeutic interventions for disease progression in Huntington's disease. Cochrane Database Syst Rev. 2009(3):CD006455. Epub 2009/07/10. doi: 10.1002/14651858.CD006455.pub2. PubMed PMID: 19588392.
  150. Bonelli RM, Wenning GK. Pharmacological management of Huntington's disease: an evidence-based review. Curr Pharm Des. 2006;12(21):2701-20. Epub 2006/07/18. PubMed PMID: 16842168.
  151. Dhanasekaran M, Ren J. The emerging role of coenzyme Q-10 in aging, neurodegeneration, cardiovascular disease, cancer and diabetes mellitus. Curr Neurovasc Res. 2005;2(5):447-59. Epub 2005/12/27.
  152. PubMed PMID: 16375724.
  153. Wu SS, Frucht SJ. Treatment of Parkinson's disease : what's on the horizon? CNS Drugs. 2005;19(9):723-43. Epub 2005/09/07. doi: 1991 [pii]. PubMed PMID: 16142989.
  154. Fosslien E. Review: molecular pathology of cyclooxygenase-2 in cancer-induced angiogenesis. Ann Clin Lab Sci. 2001;31(4):325-48. Epub 2001/11/02. PubMed PMID: 11688844.
  155. Miles MV, Patterson BJ, Chalfonte-Evans ML, Horn PS, Hickey FJ, Schapiro MB, et al. Coenzyme Q10 (ubiquinol-10) supplementation improves oxidative imbalance in children with trisomy 21. Pediatr Neurol. 2007;37(6):398-403. Epub 2007/11/21. doi: S0887-8994(07)00389-X [pii]
  156. 1016/j.pediatrneurol.2007.08.003. PubMed PMID: 18021919.
  157. Kidd PM. Neurodegeneration from mitochondrial insufficiency: nutrients, stem cells, growth factors, and prospects for brain rebuilding using integrative management. Altern Med Rev. 2005;10(4):268-93. Epub 2005/12/22. PubMed PMID: 16366737.
  158. Pepe S, Marasco SF, Haas SJ, Sheeran FL, Krum H, Rosenfeldt FL. Coenzyme Q10 in cardiovascular disease. Mitochondrion. 2007;7 Suppl:S154-67. Epub 2007/05/09. doi: S1567-7249(07)00050-5 [pii]
  159. 1016/j.mito.2007.02.005. PubMed PMID: 17485243.
  160. Quinzii CM, Hirano M. Primary and secondary CoQ(10) deficiencies in humans. Biofactors.37(5):361-5. Epub 2011/10/13. doi: 10.1002/biof.155. PubMed PMID: 21990098.
  161. Littarru GP, Tiano L, Belardinelli R, Watts GF. Coenzyme Q(10) , endothelial function, and cardiovascular disease. Biofactors.37(5):366-73. Epub 2011/06/16. doi: 10.1002/biof.154. PubMed PMID: 21674640.
  162. Laufs U, Custodis F, Bohm M. HMG-CoA reductase inhibitors in chronic heart failure: potential mechanisms of benefit and risk. Drugs. 2006;66(2):145-54. Epub 2006/02/03. doi: 6622 [pii]. PubMed PMID: 16451090.
  163. Kaliora AC, Dedoussis GV, Schmidt H. Dietary antioxidants in preventing atherogenesis. Atherosclerosis. 2006;187(1):1-17. Epub 2005/11/30. doi: S0021-9150(05)00721-5 [pii]
  164. 1016/j.atherosclerosis.2005.11.001. PubMed PMID: 16313912.
  165. Greenberg S, Frishman WH. Co-enzyme Q10: a new drug for cardiovascular disease. J Clin Pharmacol. 1990;30(7):596-608. Epub 1990/07/01. PubMed PMID: 2202752.
  166. Silver MA, Langsjoen PH, Szabo S, Patil H, Zelinger A. Effect of atorvastatin on left ventricular diastolic function and ability of coenzyme Q10 to reverse that dysfunction. Am J Cardiol. 2004;94(10):1306-10. Epub 2004/11/16. doi: S0002-9149(04)01235-4 [pii]
  167. 1016/j.amjcard.2004.07.121. PubMed PMID: 15541254.
  168. De Pinieux G, Chariot P, Ammi-Said M, Louarn F, Lejonc JL, Astier A, et al. Lipid-lowering drugs and mitochondrial function: effects of HMG-CoA reductase inhibitors on serum ubiquinone and blood lactate/pyruvate ratio. Br J Clin Pharmacol. 1996;42(3):333-7. Epub 1996/09/01. PubMed PMID: 8877024.