Protective effects of coenzyme Q10 and L-carnitine against statin-induced pancreatic mitochondrial toxicity in rats

Melina Sadighara, Jalal Pourahamad Joktaji, Valiollah Hajhashemi, Mohsen Minaiyan

Abstract


Statins are widely used in patients with hyperlipidemia and whom with high risk of cardiovascular diseases. Unfortunately, statins also exert some adverse effects on the liver and pancreas and enhance the risk of type 2 diabetes mellitus. The objective of the present research was to investigate the protective effects of coenzyme Q10 (Co-Q10) and L-carnitine (LC) on statins induced toxicity on pancreatic mitochondria in vivo. Seven groups of male Wistar rats received atorvastatin (20 mg/kg, p.o.), atorvastatin + Co-Q10 (10 mg/kg, i.p.), atorvastatin + LC (500 mg/kg, i.p.), lovastatin (80 mg/kg, p.o), lovastatin + Co-Q10 (10 mg/kg, i.p.), and lovastatin + LC (500 mg/kg, i.p.). Serum glucose and insulin levels were measured before and after two weeks of treatment, while the pancreas was removed and toxic effects of statins, as well as the protective effects of Co-Q10 and LC were assessed. The results showed that atorvastatin and lovastatin significantly increased glucose level and decreased insulin secretion. The glucose level in Co-Q10 and LC groups was significantly lower than statins alone groups. The findings also showed that statin groups had higher rate of pancreatic toxicity including higher level of reactive oxygen species production, decreased cytochrome c oxidase activity, collapse of mitochondrial membrane potential and swelling in comparison to controls. These factors were significantly diminished by co-administration of Co-Q10 or LC compared to statin groups alone. Additionally, supplements caused a significant increase in serum insulin and succinate dehydrogenase activity. Our study provided new evidence supporting beneficial effects of Co-Q10 and LC on statin-induced pancreatic toxicity.


Keywords


Statins; Diabetes mellitus; Pancreatic mitochondria; Coenzyme Q10; L-carnitine

Full Text:

PDF

References


Pradeepa R, Mohan V. Prevalence of type 2 diabetes and its complications in India and economic costs to the nation. Eur J Clin Nutr. 2017;71(7):816-824.

Ponte CD, Dang DK. Drug-Induced Diabetes. Textbook of Diabetes. 5th ed. Chichester: Wiley-Blackwell; 2017. pp. 262-272.

Van Wissen S, Smilde TJ, Trip MD, Stalenhoef AF, Kastelein JJ. Long-term safety and efficacy of high-dose atorvastatin treatment in patients with familial hypercholesterolemia. Am J Cardiol. 2005; 95(2):264-266.

Lipid modification: cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of cardiovascular disease. National Institute for Health and Care Excellence. 2014. National Clinical Guideline Center (UK). London. No. 181.

Olokoba AB, Obateru OA, Olokoba LB. Type 2 diabetes mellitus: a review of current trends. Oman Med J. 2012;27(4):269-273.

Whiting DR, Guariguata L, Weil C, Shaw J. IDF diabetes atlas: global estimates of the prevalence of diabetes for 2011 and 2030. Diabetes Res Clin Pract. 2011;94(3):311-321.

Gluba-Brzozka A, Franczyk B, Toth PP, Rysz J, Banach M. Molecular mechanisms of statin intolerance. Arch Med Sci. 2016;12(3):645-658.

Sattar NA, Ginsberg H, Ray K, Chapman MJ, Arca M, Averna M, et al. The use of statins in people at risk of developing diabetes mellitus: evidence and guidance for clinical practice. Atheroscler Suppl. 2014;15(1):1-15.

Bouitbir J, Singh F, Charles AL, Schlagowski AI, Bonifacio A, Echaniz-Laguna A, et al. Statins trigger mitochondrial reactive oxygen species-induced apoptosis in glycolytic skeletal muscle. Antioxid Redox Signal. 2016;24(2):84-98.

Ristow M, Schmeisser K. Mitohormesis: promoting health and lifespan by increased levels of reactive oxygen species (ROS). Dose Response. 2014;12(2):288-341.

Busanello ENB, Marques AC, Lander N, de Oliveira DN, Catharino RR, Oliveira HCF, et al. Pravastatin chronic treatment sensitizes hypercholesterolemic mice muscle to mitochondrial permeability transition: Protection by creatine or coenzyme Q10. Front Pharmacol. 2017;8:185.

Abdoli N, Azarmi Y, Eghbal MA. Mitigation of statins-induced cytotoxicity and mitochondrial dysfunction by L-carnitine in freshly-isolated rat hepatocytes. Res Pharm Sci. 2015;10(2):143-151.

La Guardia PG, Alberici LC, Ravagnani FG, Catharino RR, Vercesi AE. Protection of rat skeletal muscle fibers by either L-carnitine or coenzyme Q10 against statins toxicity mediated by mitochondrial reactive oxygen generation. Front Physiol. 2013;4:103.

Wood WG, Mΰller WE, Eckert GP. Statins and neuroprotection: basic pharmacology needed. Mol Neurobiol. 2014;50(1):214-220.

Montgomery MK, Turner N. Mitochondrial dysfunction and insulin resistance: an update. Endocr connect. 2015;4(1):R1-R15.

Alam MA, Rahman MM. Mitochondrial dysfunction in obesity: potential benefit and mechanism of Co-enzyme Q10 supplementation in metabolic syndrome. J Diabetes Metab Disord. 2014;13:60.

Sirtori CR. The pharmacology of statins. Pharmacol Res. 2014;88:3-11.

Gazzerro P, Proto MC, Gangemi G, Malfitano AM, Ciaglia E, Pisanti S, et al. Pharmacological actions of statins: a critical appraisal in the management of cancer. Pharmacol Rev. 2012;64(1):102-146.

Ali SA, Faddah L, Abdel-Baky A, Bayoumi A. Protective effect of L-carnitine and coenzyme Q10 on CCl4-induced liver injury in rats. Sci Pharm. 2010;78(4):881-896.

Xiang Y, Piao SG, Zou HB, Jin J, Fang MR, Lei DM, et al. L-carnitine protects against cyclosporine-induced pancreatic and renal injury in rats.Transplant Proc. 2013;45(8):3127-3134.

Chen PY, Hou CW, Shibu MA, Day CH, Pai P, Liu ZR, et al. Protective effect of Co-enzyme Q10 on doxorubicin-induced cardiomyopathy of rat hearts. Environ Toxicol. 2017;32(2):679-689.

Panonnummal R, Varkey J. Statins induced nephrotoxicity: a dose dependent study in albino rats. Int J Pharm Pharm Sci. 2014;6(11):401-406.

Coldiron AD Jr, Sanders RA, Watkins JB. Effects of combined quercetin and coenzyme Q(10) treatment on oxidative stress in normal and diabetic rats. J Biochem Mol Toxicol. 2002;16(4):197-202.

Uysal N, Yalaz G, Acikgoz O, Gonenc S, Kayatekin BM. Effect of L-carnitine on diabetogenic action of streptozotocin in rats. Neuro Endocrinol Lett. 2005;26(4):419-422.

Odinokova IV, Shalbuyeva N, Gukovskaya AS, Mareninova OA. Isolation of pancreatic mitochondria and measurement of their functional parameters. Pancreapedia: Exocrine Pancreas Knowledge Base. 2011;25:1-10.

Zhao Y, Ye L, Liu H, Xia Q, Zhang Y, Yang X, et al. Vanadium compounds induced mitochondria permeability transition pore (MPT) opening related to oxidative stress. J Inorg Biochem. 2010;104(4):371-378.

Shaki F, Hosseini MJ, Ghazi-Khansari M, Pourahmad J. Toxicity of depleted uranium on isolated rat kidney mitochondria. Biochim Biophys Acta. 2012;1820(12):1940-1950.

Shaki F, Shayeste Y, Karami M, Akbari E, Rezaei M, Ataee R. The effect of epicatechin on oxidative stress and mitochondrial damage induced by homocycteine using isolated rat hippocampus mitochondria. Res Pharm Sci. 2017;12(2):119-127.

Sadighara M, Amirsheardost Z, Minaiyan M, Hajhashemi V, Naserzadeh P, Salimi A, et al. Toxicity of atorvastatin on pancreas mitochondria: a justification for increased risk of diabetes mellitus. Basic Clin Pharmacol Toxicol. 2017;120(2): 131-137.

Carter AA, Gomes T, Camacho X, Juurlink DN, Shah BR, Mamdani MM. Risk of incident diabetes among patients treated with statins: population based study. BMJ. 2013;346:f2610.

Corpier CL, Jones PH, Suki WN, Lederer ED, Quinones MA, Schmidt SW, et al. Rhabdomyolysis and renal injury with lovastatin use: report of two cases in cardiac transplant recipients. JAMA. 1988;260(2):239-241.

Aiman U, Najmi A, Khan RA. Statin induced diabetes and its clinical implications. J Pharmacol Pharmacother. 2014;5(3):181-185.

Zaharan NL, Williams D, Bennett K. Statins and risk of treated incident diabetes in a primary care population. Br J Clin Pharmacol. 2013;75(4):1118-1124.

Cederberg H, Stančáková A, Yaluri N, Modi S, Kuusisto J, Laakso M. Increased risk of diabetes with statin treatment is associated with impaired insulin sensitivity and insulin secretion: a 6 year follow-up study of the METSIM cohort. Diabetologia. 2015;58(5):1109-1117.

follow-up study of the METSIM cohort. Diabetologia. 2015;58(5):1109-1117.

Erqou S, Lee CC, Adler AI. Statins and glycaemic control in individuals with diabetes: a systematic review and meta-analysis. Diabetologia. 2014;57(12):2444-2452.

Tiwari BK, Pandey KB, Abidi AB, Rizvi SI. Markers of oxidative stress during diabetes mellitus. J Biomark. 2013;2013: Article ID 378790, 8 pages.

Bouitbir J, Charles AL, Echaniz-Laguna A, Kindo M, Daussin F, Auwerx J, et al. Opposite effects of statins on mitochondria of cardiac and skeletal muscles: a ‘mitohormesis’ mechanism involving reactive oxygen species and PGC-1. Eur Heart J. 2012;33(11):1397-1407.

Abdoli N, Azarmi Y, Eghbal MA. Protective effects of N-acetylcysteine against the Statins cytotoxicity in freshly isolated rat hepatocytes. Adv Pharm Bull. 2014;4(3):249-254.

Kato S, Smalley S, Sadarangani A, Chen-Lin K, Oliva B, Branes J, et al. Lipophilic but not hydrophilic statins selectively induce cell death in gynaecological cancers expressing high levels of HMGCoA reductase. J Cell Mol Med. 2010;14(5):1180-1193.

Ben-Meir A, Burstein E, Borrego-Alvarez A, Chong J, Wong E, Yavorska T, et al. Coenzyme Q10 restores oocyte mitochondrial function and fertility during reproductive aging. Aging Cell. 2015;14(5):887-895.

Noh YH, Kim KY, Shim MS, Choi SH, Choi S, Ellisman MH, et al. Inhibition of oxidative stress by coenzyme Q10 increases mitochondrial mass and improves bioenergetic function in optic nerve head astrocytes. Cell Death Dis. 2013;4:e820.

Costa RA, Fernandes MP, de Souza-Pinto NC, Vercesi AE. Protective effects of l-carnitine and piracetam against mitochondrial permeability transition and PC3 cell necrosis induced by simvastatin. Eur J Pharmacol. 2013;701(1-3):82-86.

Mabuchi H, Higashikata T, Kawashiri M, Katsuda S, Mizuno M, Nohara A, et al. Reduction of serum ubiquinol-10 and ubiquinone-10 levels by atorvastatin in hypercholesterolemic patients. J Atheroscler Thromb. 2005;12(2):111-119.

Chen CC, Liou SW, Chen CC, Chen WC, Hu FR, Wang IJ, et al. Coenzyme Q10 rescues ethanol-induced corneal fibroblast apoptosis through the inhibition of caspase-2 activation. J Biol Chem. 2013;288(17):11689-11704.

Chao HH, Liu JC, Hong HJ, Lin JW, Chen CH, Cheng TH. L-carnitine reduces doxorubicin-induced apoptosis through a prostacyclin-mediated pathway in neonatal rat cardiomyocytes. Int J Cardiol. 2011;146(2):145-152.

Mohammadi-Bardbori A, Najibi A, Amirzadegan N, Gharibi R, Dashti A, Omidi M, et al. Coenzyme Q10 remarkably improves the bio-energetic function of rat liver mitochondria treated with statins. Eur J Pharmacol. 2015;762:270-274.


Refbacks

  • There are currently no refbacks.