Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
권호 표지
DOI QR코드

DOI QR Code

Effect of Coenzyme Q10 Supplementation in Statin-Treated Obese Rats

  • Choi, Hye-Kyung (Department of Preventive Pharmacy and Toxicology, College of Pharmacy, Kyung Hee University) ;
  • Won, Eun-Kyung (Department of Preventive Pharmacy and Toxicology, College of Pharmacy, Kyung Hee University) ;
  • Choung, Se-Young (Department of Preventive Pharmacy and Toxicology, College of Pharmacy, Kyung Hee University)
  • Received : 2015.07.01
  • Accepted : 2015.09.24
  • Published : 2016.03.01
Download PDF
⟨ Previous Next ⟩

Abstract

Statins, HMG-CoA reductase inhibitors, are known to cause serious muscle injuries (e.g. myopathy, myositis and rhabdomyolysis), and these adverse effects can be rescued by co-administration of coenzyme $Q_{10}$ ($CoQ_{10}$) with statins. The goal of the current research is to assess the efficacy of combined treatment of $CoQ_{10}$ with Atorvastatin for hyperlipidemia induced by high-fat diet in SD rats. 4-week-old Sprague-Dawley male rats were fed normal diet or high-fat diet for 6 weeks. Then, rats were treated with either Statin or Statin with various dosages of $CoQ_{10}$ (30, 90 or 270 mg/kg/day, p.o.) for another 6 weeks. Compared to Statin only treatment, $CoQ_{10}$ supplementation significantly reduced creatine kinase and aspartate aminotransferase levels in serum which are markers for myopathy. Moreover, $CoQ_{10}$ supplementation with Statin further reduced total fat, triglycerides, total cholesterol, and low-density lipoprotein-cholesterol. In contrast, the levels of high-density lipoprotein-cholesterol and $CoQ_{10}$ were increased in the $CoQ_{10}$ co-treated group. These results indicate that $CoQ_{10}$ treatment not only reduces the side effects of Statin, but also has an anti-obesity effect. Therefore an intake of supplementary $CoQ_{10}$ is helpful for solving problem of obese metabolism, so the multiple prescription of $CoQ_{10}$ makes us think a possibility that can be solved in being contiguous to the obesity problem, a sort of disease of the obese metabolism.

Keywords

References

  1. Alberts, A. W., Chen, J., Kuron, G., Hunt, V., Huff, J., Hoffman, C., Rothrock, J., Lopez, M., Joshua, H., Harris, E., Patchett, A., Monaghan, R., Currie, S., Stapley, E., Albers-Schonberg, G., Hensens, O., Hirshfield, J., Hoogsteen, K., Liesch, J. and Springer, J. (1980). Mevinolin: a highly potent competitive inhibitor of hydroxymethylglutaryl-coenzyme A reductase and a cholesterollowering agent. Proc. Natl. Acad. Sci. U.S.A. 77, 3957-3961. https://doi.org/10.1073/pnas.77.7.3957
  2. Anand, S. S. (2003) Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. Law MR, Wald NJ, Rudnicka AR. BMJ 2003; 326: 1407-408. Vasc. Med. 8, 289-290. https://doi.org/10.1191/1358863x03vm518xx
  3. Berthold, H. K., Naini, A., Di Mauro, S., Hallikainen, M., Gylling, H., Krone, W. and Gouni-Berthold, I. (2006) Effect of ezetimibe and/or simvastatin on coenzyme Q10 levels in plasma: a randomised trial. Drug Saf. 29, 703-712. https://doi.org/10.2165/00002018-200629080-00007
  4. Bosch, X., Poch, E. and Grau, J. M. (2009) Rhabdomyolysis and acute kidney injury. N. Engl. J. Med. 361, 62-72. https://doi.org/10.1056/NEJMra0801327
  5. Buchholz, U., Mouzin, E., Dickey, R., Moolenaar, R., Sass, N. and Mascola, L. (2000) Haff disease: from the Baltic Sea to the U.S. shore. Emerg. Infect. Dis. 6, 192-195. https://doi.org/10.3201/eid0602.000215
  6. Caso, G., Kelly, P., McNurlan, M. A. and Lawson, W. E. (2007) Effect of coenzyme q10 on myopathic symptoms in patients treated with statins. Am. J. Cardiol. 99, 1409-1412. https://doi.org/10.1016/j.amjcard.2006.12.063
  7. Crane, F. L. (2001) Biochemical functions of coenzyme Q10. J. Am. Coll. Nutr. 20, 591-598. https://doi.org/10.1080/07315724.2001.10719063
  8. Deichmann, R., Lavie, C. and Andrews, S. (2010) Coenzyme q10 and statin-induced mitochondrial dysfunction. Ochsner J. 10, 16-21.
  9. Delbosc, S., Cristol, J. P., Descomps, B., Mimran, A. and Jover, B. (2002) Simvastatin prevents angiotensin II-induced cardiac alteration and oxidative stress. Hypertension 40, 142-147. https://doi.org/10.1161/01.HYP.0000024348.87637.6F
  10. Diebold, B. A., Bhagavan, N. V. and Guillory, R. J. (1994) Influences of lovastatin administration on the respiratory burst of leukocytes and the phosphorylation potential of mitochondria in guinea pigs. Biochim. Biophys Acta 1200, 100-108. https://doi.org/10.1016/0304-4165(94)90123-6
  11. Franc, S., Dejager, S., Bruckert, E., Chauvenet, M., Giral, P. and Turpin, G. (2003) A comprehensive description of muscle symptoms associated with lipid-lowering drugs. Cardiovasc. Drugs Ther 17, 459-465. https://doi.org/10.1023/B:CARD.0000015861.26111.ab
  12. Giboney, P. T. (2005) Mildly elevated liver transaminase levels in the asymptomatic patient. Am. Fam. Physician 71, 1105-1110.
  13. Golomb, B. A. and Evans, M. A. (2008) Statin adverse effects : a review of the literature and evidence for a mitochondrial mechanism. Am. J. Cardiovasc. Drugs 8, 373-418. https://doi.org/10.2165/0129784-200808060-00004
  14. Huerta-Alardin, A. L., Varon, J. and Marik, P. E. (2005) Bench-to-bedside review: Rhabdomyolysis -- an overview for clinicians. Crit. Care 9, 158-169. https://doi.org/10.1186/cc3221
  15. Istvan, E. S. and Deisenhofer, J. (2001) Structural mechanism for statin inhibition of HMG-CoA reductase. Science 292, 1160-1164. https://doi.org/10.1126/science.1059344
  16. Kim, W. S., Kim, M. M., Choi, H. J., Yoon, S. S., Lee, M. H., Park, K., Park, C. H. and Kang, W. K. (2001) Phase II study of high-dose lovastatin in patients with advanced gastric adenocarcinoma. Invest. New Drugs 19, 81-83. https://doi.org/10.1023/A:1006481423298
  17. Laaksonen, R., Jokelainen, K., Sahi, T., Tikkanen, M. J. and Himberg, J. J. (1995) Decreases in serum ubiquinone concentrations do not result in reduced levels in muscle tissue during short-term simvastatin treatment in humans. Clin. Pharmacol. Ther. 57, 62-66. https://doi.org/10.1016/0009-9236(95)90266-X
  18. Littarru, G. P. and Langsjoen, P. (2007) Coenzyme Q10 and statins: biochemical and clinical implications. Mitochondrion 7 Suppl, S168-S174. https://doi.org/10.1016/j.mito.2007.03.002
  19. Littarru, G. P. and Tiano, L. (2007) Bioenergetic and antioxidant properties of coenzyme Q10: recent developments. Mol. Biotechnol. 37, 31-37. https://doi.org/10.1007/s12033-007-0052-y
  20. Manoukian, A. A., Bhagavan, N. V., Hayashi, T., Nestor, T. A., Rios, C. and Scottolini, A. G. (1990) Rhabdomyolysis secondary to lovastatin therapy. Clin. Chem. 36, 2145-2147.
  21. Marcoff, L. and Thompson, P. D. (2007) The role of coenzyme Q10 in statin-associated myopathy: a systematic review. J. Am. Coll. Cardiol. 49, 2231-2237. https://doi.org/10.1016/j.jacc.2007.02.049
  22. Nakahara, K., Kuriyama, M., Sonoda, Y., Yoshidome, H., Nakagawa, H., Fujiyama, J., Higuchi, I. and Osame, M. (1998) Myopathy induced by HMG-CoA reductase inhibitors in rabbits: a pathological, electrophysiological, and biochemical study. Toxicol. Appl. Pharmacol. 152, 99-106. https://doi.org/10.1006/taap.1998.8491
  23. Niska, R. and Han, B. (2009) Statins for secondary cardiovascular disease prevention for older primary care patients. J. Natl. Med. Assoc. 101, 705-710. https://doi.org/10.1016/S0027-9684(15)30980-9
  24. Quinzii, C. M., DiMauro, S. and Hirano, M. (2007) Human coenzyme Q10 deficiency. Neurochem. Res. 32, 723-727. https://doi.org/10.1007/s11064-006-9190-z
  25. Ray, K. K., Seshasai, S. R., Erqou, S., Sever, P., Jukema, J. W., Ford, I. and Sattar, N. (2010) Statins and all-cause mortality in high-risk primary prevention: a meta-analysis of 11 randomized controlled trials involving 65,229 participants. Arch. Intern. Med. 170, 1024-1031. https://doi.org/10.1001/archinternmed.2010.182
  26. Reeves, P. G., Nielsen, F. H. and Fahey, G. C. Jr. (1993) AIN-93 purified diets for laboratory rodents: final report of the American Institute of Nutrition ad hoc writing committee on the reformulation of the AIN-76A rodent diet. J. Nutr. 123,1939-1951. https://doi.org/10.1093/jn/123.11.1939
  27. Rundek, T., Naini, A., Sacco, R., Coates, K. and DiMauro, S. (2004) Atorvastatin decreases the coenzyme Q10 level in the blood of patients at risk for cardiovascular disease and stroke. Arch. Neurol. 61, 889-892. https://doi.org/10.1001/archneur.61.6.889
  28. Satoh, K. and Ichihara, K. (2000) Lipophilic HMG-CoA reductase inhibitors increase myocardial stunning in dogs. J. Cardiovasc. Pharmacol. 35, 256-262. https://doi.org/10.1097/00005344-200002000-00012
  29. Sehayek, E., Butbul, E., Avner, R., Levkovitz, H. and Eisenberg, S. (1994) Enhanced cellular metabolism of very low density lipoprotein by simvastatin. A novel mechanism of action of HMG-CoA reductase inhibitors. Eur. J. Clin. Invest. 24, 173-178. https://doi.org/10.1111/j.1365-2362.1994.tb00984.x
  30. Siciliano, G., Volpi, L., Piazza, S., Ricci, G., Mancuso, M. and Murri, L. (2007) Functional diagnostics in mitochondrial diseases. Biosci. Rep. 27, 53-67. https://doi.org/10.1007/s10540-007-9037-0
  31. Silva, M. A., Swanson, A. C., Gandhi, P. J. and Tataronis, G. R. (2006) Statin-related adverse events: a meta-analysis. Clin. Ther. 28, 26-35. https://doi.org/10.1016/j.clinthera.2006.01.005
  32. Stancu, C. and Sima, A. (2001) Statins: mechanism of action and effects. J. Cell Mol. Med. 5, 378-387. https://doi.org/10.1111/j.1582-4934.2001.tb00172.x
  33. Thibault, A., Samid, D., Tompkins, A. C., Figg, W. D., Cooper, M. R., Hohl, R. J., Trepel, J., Liang, B., Patronas, N., Venzon, D. J., Reed, E. and Myers, C. E. (1996) Phase I study of lovastatin, an inhibitor of the mevalonate pathway, in patients with cancer. Clin. Cancer Res. 2, 483-491.
  34. Thompson, P. D., Clarkson, P. and Karas, R. H. (2003) Statin-associated myopathy. JAMA 289, 1681-1690. https://doi.org/10.1001/jama.289.13.1681
  35. Vanholder, R., Sever, M. S., Erek, E. and Lameire, N. (2000) Rhabdomyolysis. J. Am. Soc. Nephrol. 11, 1553-1561.
  36. Zita, C., Overvad, K., Mortensen, S. A., Sindberg, C. D., Moesgaard, S. and Hunter, D. A. (2003) Serum coenzyme Q10 concentrations in healthy men supplemented with 30 mg or 100 mg coenzyme Q10 for two months in a randomised controlled study. Biofactors 18, 185-193. https://doi.org/10.1002/biof.5520180221

Cited by

  1. Effects of Coenzyme Q10 on Statin‐Induced Myopathy: An Updated Meta‐Analysis of Randomized Controlled Trials vol.7, pp.19, 2018, https://doi.org/10.1161/JAHA.118.009835
  2. Effect of L-carnitine on the skeletal muscle contractility in simvastatin-induced myopathy in rats vol.29, pp.5, 2018, https://doi.org/10.1515/jbcpp-2017-0156
  3. Familial Hypercholesterolemia: New Horizons for Diagnosis and Effective Management vol.9, pp.1663-9812, 2018, https://doi.org/10.3389/fphar.2018.00707
  4. Ontology-based systematical representation and drug class effect analysis of package insert-reported adverse events associated with cardiovascular drugs used in China vol.7, pp.None, 2016, https://doi.org/10.1038/s41598-017-12580-4
  5. Atorvastatin in nano-particulate formulation abates muscle and liver affliction when coalesced with coenzyme Q10 and/or vitamin E in hyperlipidemic rats vol.203, pp.None, 2016, https://doi.org/10.1016/j.lfs.2018.04.034
  6. Effect of SLCO1B1 T521C on Statin-induced Myotoxicity: A Systematic Review and Meta-analysis vol.28, pp.4, 2018, https://doi.org/10.24304/kjcp.2018.28.4.320
  7. Assessment of bee venom therapy in animal model of statin-induced myopathy vol.55, pp.1, 2016, https://doi.org/10.1186/s41983-019-0120-9
  8. Pyrroloquinoline quinone attenuates obesity associated low grade inflammation vol.16, pp.None, 2016, https://doi.org/10.1016/j.obmed.2019.100134