vedomostiregmedРегуляторные исследования и экспертиза лекарственных средствRegulatory Research and Medicine Evaluation3034-30623034-3453Federal State Budgetary Institution ‘Scientific Centre for Expert Evaluation of Medicinal Products’ of the Ministry of Health of the Russian Federation (FSBI ‘SCEEMP’)10.30895/1991-2919-2019-9-3-146-152vedomostiregmed-251Research ArticleОБЗОРЫREVIEWSЗначение редокс-статуса коэнзима Q10 как биомаркера окислительного стрессаEvaluation of Coenzyme Q10 Redox Status as a Biomarker of Oxidative Stresshttps://orcid.org/0000-0003-0448-3612ГорошкоО. А.GoroshkoO. A.

Горошко Ольга Александровна, канд. фарм. наук. 

Петровский б-р, д. 8, стр. 2, Москва, 127051

 

Olga A. Goroshko, Cand. Sci. (Pharm.). 

8/2 Petrovsky Blvd, Moscow 127051

olga_goroshko@mail.ruhttps://orcid.org/0000-0003-3650-6014КрасныхЛ. М.KrasnykhL. M.

Красных Людмила Михайловна, канд. биол. наук.

Петровский б-р, д. 8, стр. 2, Москва, 127051

Lyudmila M. Krasnykh, Cand. Sci. (Biol.)

8/2 Petrovsky Blvd, Moscow 127051

lkrasnykhlm59@mail.ruhttps://orcid.org/0000-0002-5112-6928КукесВ. Г.KukesV. G.

Кукес Владимир Григорьевич, академик РАН, д-р мед. наук, проф. 

Петровский б-р, д. 8, стр. 2, Москва, 127051

Vladimir G. Kukes, Academician of RAS, Dr. Sci. (Med.), Professor.

8/2 Petrovsky Blvd, Moscow 127051

elmed@yandex.ruhttps://orcid.org/0000-0003-2036-7435ЗозинаВ. И.ZozinaV. I.

Зозина Владлена Игоревна

Трубецкая ул., д. 8, стр. 2, Москва, 119991

Vladlena I. Zozina

8/2 Trubetskaya St., Moscow 119991

elmed@yandex.ruФедеральное государственное бюджетное учреждение «Научный центр экспертизы средств медицинского применения» Министерства здравоохранения Российской ФедерацииРоссияScientific Centre for Expert Evaluation of Medicinal ProductsRussian FederationФедеральное государственное автономное образовательное учреждение высшего образования «Первый Московский государственный медицинский университет им. И. М. Сеченова» Министерства здравоохранения Российской ФедерацииРоссияI. M. Sechenov First Moscow State Medical UniversityRussian Federation20192407201993146152Copyright © Горошко О.А., Красных Л.М., Кукес В.Г., Зозина В.И., 20192019Горошко О.А., Красных Л.М., Кукес В.Г., Зозина В.И.Goroshko O.A., Krasnykh L.M., Kukes V.G., Zozina V.I.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.vedomostincesmp.ru/jour/article/view/251

Рассмотрена роль убихинона как редокс-молекулы, функциями которой являются перенос электронов в дыхательной цепи митохондрии и регенерация эндогенных антиоксидантов. Изменение редокс-путей электронов вызывает неконтролируемую выработку активных форм кислорода, что приводит к окислительному стрессу и развитию патологий. Цель работы — выявление содержания коэнзима Q10 и значения его редокс-статуса в организме как биомаркера окислительного стресса при различных патологиях, для чего были оценены и обобщены данные о динамике концентраций окисленной, восстановленной формы и общего убихинона при различных патологиях. Содержание общего убихинона в сыворотке крови пациентов с хронической сердечной недостаточностью было снижено (0,68 мкмоль/л) по сравнению с контрольной группой (0,97 мкмоль/л). Редокс-статус, выраженный как отношение концентрации [убихинол]/[убихинон], снижался у пациентов с ишемической болезнью сердца (0,49 ± 0,34), диабетом (0,26 ± 0,16) по сравнению со здоровыми лицами (1,23–1,41). При этом наблюдалась отрицательная корреляция с малоновым диальдегидом. Проведен анализ возможности оценки эффективности статинотерапии по содержанию убихинона в плазме крови пациентов. У пациентов с гиперлипидемией, получавших статины, были достоверно снижены концентрация убихинола после приема препарата (с 0,81 до 0,46 мкг/мл) и соотношение [убихинон]/[общий убихинон] (с 11 до 10 %), что подтверждает потенциальный механизм возникновения статин-ассоциированных поражений мышц. Таким образом, редокс-статус коэнзима Q10, а также концентрация окисленного, восстановленного и общего убихинона могут быть эффективными биомаркерами окислительного стресса при сердечно-сосудистых заболеваниях, диабете, а также важным показателем при оценке эффективности лечения гиперлипидемии.

The article examines the role of ubiquinone as a redox molecule whose functions consist in electron transport in the mitochondrial respiratory chain and regeneration of endogenous antioxidants. Changes in electron redox pathways cause uncontrolled release of reactive oxygen species, which leads to oxidative stress and development of pathologies. The objective of the study was to determine the content of coenzyme Q10 and its redox status in the human body as a biomarker of oxidative stress in various pathologies. This was achieved by assessing and consolidating data on changes in concentrations of the oxidized, reduced ubiquinone forms and total ubiquinone in various pathologies. Total serum ubiquinone was reduced in patients with chronic heart failure (0.68 μmol/L) compared with the control group (0.97 μmol/L). The redox status, expressed as the [ubiquinol]/ [ubiquinone] concentration ratio, decreased in patients with coronary heart disease (0.49 ± 0.34), diabetes (0.26 ± 0.16) compared with the healthy subjects (1.23–1.41). A negative correlation with malonic dialdehyde was observed. The authors analysed the possibility of assessing the efficacy of statin therapy by plasma ubiquinone concentration in patients. Patients with hyperlipidemia who received statins showed a statistically significant reduction in ubiquinol concentration after taking the drug (from 0.81 to 0.46 μg/mL) and the [ubiquinone]/[total ubiquinone] ratio (from 11 to 10 %), which confirms the potential mechanism of statinassociated muscle injury development. Thus, coenzyme Q10 redox status, as well as the concentrations of oxidized, reduced and total ubiquinone can be effective biomarkers of oxidative stress in cardiovascular diseases, diabetes, as well as an important indicator in evaluating the efficacy of hyperlipidemia treatment.

убихинонубихинолкоэнзим Q10редокс-статуссердечно-сосудистые патологиигиперлипидемиястатиныubiquinoneubiquinolcoenzyme Q10redox statuscardiovascular pathologieshyperlipidemiastatinsРабота выполнена в рамках государственного задания ФГБУ «НЦЭСМП» Минздрава России № 056-00154-19-00 на проведение прикладных научных исследований (номер государственного учета НИР AAAA-A18-118021590049-0).The study reported in this publication was carried out as part of a publicly funded research project No. 056-00154-19-00 and was supported by the Scientific Centre for Expert Evaluation of Medicinal Products (R&D public accounting No. AAAA-A18-118021590049-0).ReferencesCrane FL. Biochemical functions of Coenzyme Q10. J Am Coll Nutr. 2001;20(6):591–98. PMID: 11771674Crane FL. Biochemical functions of Coenzyme Q10. J Am Coll Nutr. 2001;20(6):591–98. PMID: 11771674Ernster L, Dallner G. Biochemical, physiological and medical aspects of ubiquinone function. Biochim Biophys Acta. 1995;1271(1):195– 204. https://doi.org/10.1016/0925-4439(95)00028-3Ernster L, Dallner G. Biochemical, physiological and medical aspects of ubiquinone function. Biochim Biophys Acta. 1995;1271(1):195– 204. https://doi.org/10.1016/0925-4439(95)00028-3Belliere J, Devun F, Cottet-Rousselle C, Batandier C, Leverve X, Fontaine E. Prerequisites for ubiquinone analogs to prevent mitochondrial permeability transition-induced cell death. J Bioenerg Biomembr. 2012;44(1):207–12. https://doi.org/10.1007/s10863-012-9434-3Belliere J, Devun F, Cottet-Rousselle C, Batandier C, Leverve X, Fontaine E. Prerequisites for ubiquinone analogs to prevent mitochondrial permeability transition-induced cell death. J Bioenerg Biomembr. 2012;44(1):207–12. https://doi.org/10.1007/s10863-012-9434-3Stocker R, Bowry VW, Frei B. Ubiquinol-10 protects human low density lipoprotein more efficiently against lipid peroxidation than does alpha-tocopherol. Proc Natl Acad Sci USA. 1991;88(5):1646–50. https://doi.org/10.1073/pnas.88.5.1646Stocker R, Bowry VW, Frei B. Ubiquinol-10 protects human low density lipoprotein more efficiently against lipid peroxidation than does alpha-tocopherol. Proc Natl Acad Sci USA. 1991;88(5):1646–50. https://doi.org/10.1073/pnas.88.5.1646Мартинович ГГ, Черенкевич СН. Окислительно-восстановительные процессы в клетках: Монография. Минск: БГУ; 2008.Martinovich GG, Cherenkevich SN. Oxidation-reduction processes in cells: Monograph. Minsk: BSU; 2008 (In Russ.)Miles MV, Horn PS, Morrison JA, Tang PH, DeGrauw T, Pesce AJ. Plasma coenzyme Q10 reference intervals, but not redox status, are affected by gender and race in self-reported healthy adults. Clin Chim Acta. 2003;332(1–2):123–32. https://doi.org/10.1016/S0009-8981(03)00137-2Miles MV, Horn PS, Morrison JA, Tang PH, DeGrauw T, Pesce AJ. Plasma coenzyme Q10 reference intervals, but not redox status, are affected by gender and race in self-reported healthy adults. Clin Chim Acta. 2003;332(1–2):123–32. https://doi.org/10.1016/S0009-8981(03)00137-2Niklowitz P, Menke T, Andler W, Okun JG. Simultaneous analysis of coenzyme Q10 in plasma, erythrocytes and platelets: comparison of the antioxidant level in blood cells and their environment in healthy children and after oral supplementation in adults. Clin Chim Acta. 2004;342(1–2):219–26. https://doi.org/10.1016/j.cccn.2003.12.020Niklowitz P, Menke T, Andler W, Okun JG. Simultaneous analysis of coenzyme Q10 in plasma, erythrocytes and platelets: comparison of the antioxidant level in blood cells and their environment in healthy children and after oral supplementation in adults. Clin Chim Acta. 2004;342(1–2):219–26. https://doi.org/10.1016/j.cccn.2003.12.020Tomasetti M, Alleva R, Solenghi MD, Littarru GP. Distribution of antioxidants among blood components and lipoproteins: significance of lipids/CoQ10 ratio as a possible marker of increased risk for atherosclerosis. Biofactors. 1999;9(2–4):231–40. https://doi.org/10.1002/biof.5520090218Tomasetti M, Alleva R, Solenghi MD, Littarru GP. Distribution of antioxidants among blood components and lipoproteins: significance of lipids/CoQ10 ratio as a possible marker of increased risk for atherosclerosis. Biofactors. 1999;9(2–4):231–40. https://doi.org/10.1002/biof.5520090218Черенкевич СН, Мартинович ГГ, Мартинович ИВ, Горудко ИВ, Шамова ЕВ. Редокс-регуляция клеточной активности: концепции и механизмы. Весцi Нацыянальнай акадэмii навук Беларусi. Серыя бiялагiчных навук. 2013;(1):92–108.Cherenkevich SN, Martinovich YY, Martinovich IV, Gorudko IV, Shamova EV. Redox regulation of cellular activity: concepts and mechanisms. Vestsi Natsiyanalnay akademii navuk Belarusi. Seriya biyalagichnykh navuk = Proceedings of the National Academy of Sciences of Belarus. Series of Biological Sciences. 2013;(1):92–108 (In Russ.)Jones DP. Redox theory of aging. Redox Biol. 2015;5(2):71–9. https://doi.org/10.1016/j.redox.2015.03.004Jones DP. Redox theory of aging. Redox Biol. 2015;5(2):71–9. https://doi.org/10.1016/j.redox.2015.03.004Прадедова ЕВ, Нимаева ОД, Саляев РК. Редокс-процессы в биологических системах. Физиология растений. 2017;64(6):433–45. https://doi.org/10.1134/S1021443717050107Pradedova EV, Nimaev OD, Salyaev RK. Redox processes in biological systems. Fiziologiya rasteniy = Plant Physiology. 2017;64(6):433– 45 (In Russ.) https://doi.org/10.1134/S1021443717050107Николаева ЕА, Харабадзе МН, Золкина ИВ, Кулагина ТЕ, Васина ТН, Ставцева СН и др. Диагностическое значение уровня коэнзима Q10 в крови у детей с митохондриальными заболеваниями. Российский вестник перинатологии и педиатрии. 2015;60(5):71–5.Nikolaeva EA, Kharabadze MN, Zolkina IV, Kulagina TE, Vasina TN, Stavtseva SN, et al. Diagnostic value of blood coenzyme Q10 levels in children with mitochondrial diseases. Rossiyskiy vestnik perinatologii i pediatrii = Russian Bulletin of Perinatology and Pediatrics. 2015;60(5):71–5 (In Russ.)Contin M, Flor S, Martinefski M, Lucangioli S, Tripodi V. New analytical strategies applied to the determination of Coenzyme Q10 in biological matrix. Methods Mol Biol. 2015;1208:409–20. https://doi.org/10.1007/978-1-4939-1441-8_29Contin M, Flor S, Martinefski M, Lucangioli S, Tripodi V. New analytical strategies applied to the determination of Coenzyme Q10 in biological matrix. Methods Mol Biol. 2015;1208:409–20. https://doi.org/10.1007/978-1-4939-1441-8_29Giordano FJ. Oxygen, oxidative stress, hypoxia and heart failure. J Clin Invest. 2005; 115(3):500–8. https://doi.org/10.1172/JCI24408Giordano FJ. Oxygen, oxidative stress, hypoxia and heart failure. J Clin Invest. 2005; 115(3):500–8. https://doi.org/10.1172/JCI24408Mortensen SA. Overview on Coenzyme Q10 as adjunctive therapy in chronic heart failure. Rationale, design and end-points of «Q-symbio» — a multinational trial. Biofactors. 2003;18(1–4):79–89. https://doi.org/10.1172/JCI24408Mortensen SA. Overview on Coenzyme Q10 as adjunctive therapy in chronic heart failure. Rationale, design and end-points of «Q-symbio» — a multinational trial. Biofactors. 2003;18(1–4):79–89. https://doi.org/10.1172/JCI24408Molyneux SL, Florkowski CM, George PM, Pilbrow AP, Frampton CM, Lever M., et al. Coenzyme Q10: an independent predictor of mortality in chronic heart failure. J Am Coll Cardiol. 2008;52(18):1435–41. https://doi.org/10.1016/j.jacc.2008.07.044Molyneux SL, Florkowski CM, George PM, Pilbrow AP, Frampton CM, Lever M., et al. Coenzyme Q10: an independent predictor of mortality in chronic heart failure. J Am Coll Cardiol. 2008;52(18):1435–41. https://doi.org/10.1016/j.jacc.2008.07.044Pepe S, Marasco SF, Haas SJ, Sheeran FL, Krum H, Rosenfeldt FL. Coenzyme Q10 in cardiovascular disease. Mitochondrion. 2007;(7):154–67. https://doi.org/10.1016/j.mito.2007.02.005Pepe S, Marasco SF, Haas SJ, Sheeran FL, Krum H, Rosenfeldt FL. Coenzyme Q10 in cardiovascular disease. Mitochondrion. 2007;(7):154–67. https://doi.org/10.1016/j.mito.2007.02.005Yalcin A, Kilin E, Sagcan A, Kultursa H. Coenzyme Q10 concentrations in coronary artery disease. Clin Biochem. 2004;37:706–9. https://doi.org/10.1016/j.clinbiochem.2004.02.008Yalcin A, Kilin E, Sagcan A, Kultursa H. Coenzyme Q10 concentrations in coronary artery disease. Clin Biochem. 2004;37:706–9. https://doi.org/10.1016/j.clinbiochem.2004.02.008Kaya Y, Çebi A, Söylemez N, Demir H, Alp HH, Bakan E. Correlations between oxidative DNA damage, oxidative stress and coenzyme Q10 in patients with coronary artery disease. Int J Med Sci. 2012;9(8):621–26. https://doi.org/10.7150/ijms.4768Kaya Y, Çebi A, Söylemez N, Demir H, Alp HH, Bakan E. Correlations between oxidative DNA damage, oxidative stress and coenzyme Q10 in patients with coronary artery disease. Int J Med Sci. 2012;9(8):621–26. https://doi.org/10.7150/ijms.4768Lee BJ, Lin YC, Huang YC, Ko YW, Hsia S, Lin PT. The relationship between coenzyme Q10, oxidative stress, and antioxidant enzymes activities and coronary artery disease. Scientific World Journal. 2012;2012:1–8. http://doi.org/10.1100/2012/792756Lee BJ, Lin YC, Huang YC, Ko YW, Hsia S, Lin PT. The relationship between coenzyme Q10, oxidative stress, and antioxidant enzymes activities and coronary artery disease. Scientific World Journal. 2012;2012:1–8. http://doi.org/10.1100/2012/792756Kontush A, Schippling S, Spranger T, Beisiegel U. Plasma ubiquinol-10 as a marker for disease: is the assay worthwhile? Biofactors. 1999;9(2–4):225–9. https://doi.org/10.1002/biof.5520090217Kontush A, Schippling S, Spranger T, Beisiegel U. Plasma ubiquinol-10 as a marker for disease: is the assay worthwhile? Biofactors. 1999;9(2–4):225–9. https://doi.org/10.1002/biof.5520090217Sharma A, Fonarow GC, Butler J, Ezekowitz JA, Felker GM. Coenzyme Q10 and heart failure: a state-of-the-art review. Circ Heart Fail. 2016;9(4):e002639. https://doi.org/10.1161/CIRCHEARTFAILURE.115.002639Sharma A, Fonarow GC, Butler J, Ezekowitz JA, Felker GM. Coenzyme Q10 and heart failure: a state-of-the-art review. Circ Heart Fail. 2016;9(4):e002639. https://doi.org/10.1161/CIRCHEARTFAILURE.115.002639Драпкина ОМ, Чернова ЕМ, Корнеева ОН. Статины и миопатия: молекулярные механизмы. Рациональная фармакотерапия в кардиологии. 2012;8(3):469–73.Drapkina OM, Chernova EM, Korneevа ON. Statins and myopathy: molecular mechanisms. Ratsional’naya farmakoterapiya v kardiologii = Rational Pharmacotherapy in Cardiology. 2012;8(3):469–73 (In Russ.)Румянцев НА, Кукес ВГ, Казаков РЕ, Румянцев АА, Сычев ДА. Использование фармакогенетического тестирования для предотвращения нежелательных лекарственных реакций при терапии статинами. Терапевтический архив. 2017;89(1):82–7. https://doi.org/10.17116/terarkh201789182-87Rumyantsev NA, Kukes VG, Kazakov RE, Rumyantsev AA, Sychev DA. Use of pharmacogenetic testing to prevent undesirable drug reactions during statin therapy. Terapevticheskiy arkhiv = Therapeutic Archive. 2017;89(1):82–7 (In Russ.) https://doi.org/10.17116/terarkh201789182-87Mabuchi 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):111–9. https://doi.org/10.5551/jat.12.111Mabuchi 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):111–9. https://doi.org/10.5551/jat.12.111Rundek T, Naini A, Sacco R, Coates K, DiMauro S. Atorvastatin decreases the Coenzyme Q10 level in the blood of patients at risk for cardiovascular disease and stroke. Arch Neurol. 2004;61(6):889–92. https://doi.org/10.1001/archneur.61.6.889Rundek T, Naini A, Sacco R, Coates K, DiMauro S. Atorvastatin decreases the Coenzyme Q10 level in the blood of patients at risk for cardiovascular disease and stroke. Arch Neurol. 2004;61(6):889–92. https://doi.org/10.1001/archneur.61.6.889Larsen S, Stride N, Hey-Mogensen M, Hansen CN. Bang LE, Bundgaard H, et al. Simvastatin effects on skeletal muscle relation to decreased mitochondrial function and glucose intolerance. J Am Coll Cardiol. 2013;61(1):44–53. https://doi.org/10.1016/j.jacc.2012.09.036Larsen S, Stride N, Hey-Mogensen M, Hansen CN. Bang LE, Bundgaard H, et al. Simvastatin effects on skeletal muscle relation to decreased mitochondrial function and glucose intolerance. J Am Coll Cardiol. 2013;61(1):44–53. https://doi.org/10.1016/j.jacc.2012.09.036Caso 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. https://doi.org/10.1016/j.amjcard.2006.12.063Caso 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. https://doi.org/10.1016/j.amjcard.2006.12.063Marcoff L, Thompson PD. The role of coenzyme Q10 in statin-associated myopathy: a systematic review. J Am Coll Cardiol. 2007;49(23):2231–7. https://doi.org/10.1016/j.jacc.2007.02.049Marcoff L, Thompson PD. The role of coenzyme Q10 in statin-associated myopathy: a systematic review. J Am Coll Cardiol. 2007;49(23):2231–7. https://doi.org/10.1016/j.jacc.2007.02.049Blescke B, Wllis R, Anthony M, Casselberry N, Datwani M, Uhley VE. The effect of pravastatin and atorvastatin on coenzyme Q10. Am Heart J. 2001;142(2):E2. https://doi.org/10.1067/mhj.2001.116762Blescke B, Wllis R, Anthony M, Casselberry N, Datwani M, Uhley VE. The effect of pravastatin and atorvastatin on coenzyme Q10. Am Heart J. 2001;142(2):E2. https://doi.org/10.1067/mhj.2001.116762Qu H, Meng Y, Chai H, Liang F, Zhang JY, Gao Z, Shi DZ. The effect of statin treatment on circulating coenzyme Q10 concentrations: an updated meta-analysis of randomized controlled trials. Eur J Med Res. 2018;23(1):57. https://doi.org/10.1186/s40001-018-0353-6Qu H, Meng Y, Chai H, Liang F, Zhang JY, Gao Z, Shi DZ. The effect of statin treatment on circulating coenzyme Q10 concentrations: an updated meta-analysis of randomized controlled trials. Eur J Med Res. 2018;23(1):57. https://doi.org/10.1186/s40001-018-0353-6Sourris KC, Harcourt BE, Tang PH, Morley AL, Huynh K, Penfold SA, et al. Ubiquinone (coenzyme Q10) prevents renal mitochondrial dysfunction in an experimental model of type 2 diabetes. Free Radic Biol Med. 2012;52(3):716–23. https://doi.org/10.1016/j.freeradbiomed.2011.11.017Sourris KC, Harcourt BE, Tang PH, Morley AL, Huynh K, Penfold SA, et al. Ubiquinone (coenzyme Q10) prevents renal mitochondrial dysfunction in an experimental model of type 2 diabetes. Free Radic Biol Med. 2012;52(3):716–23. https://doi.org/10.1016/j.freeradbiomed.2011.11.017Ates O, Bilen H, Keles S, Alp HH, Keleş MS, Yildirim K, et al. Plasma coenzyme Q10 levels in type 2 diabetic patients with retinopathy. Int J Ophthalmol. 2013;6(5):675–9. https://doi.org/10.3980/j.issn.2222-3959.2013.05.24Ates O, Bilen H, Keles S, Alp HH, Keleş MS, Yildirim K, et al. Plasma coenzyme Q10 levels in type 2 diabetic patients with retinopathy. Int J Ophthalmol. 2013;6(5):675–9. https://doi.org/10.3980/j.issn.2222-3959.2013.05.24

The authors declare that there are no conflicts of interest present.