Skip to main content
SpringerLink
Log in

Antioxidants decreases the intensification of low density lipoprotein in vivo peroxidation during therapy with statins

  • Chapter
Biochemistry of Diabetes and Atherosclerosis

Part of the book series: Developments in Molecular and Cellular Biochemistry ((DMCB,volume 42))

Abstract

The oxidative modification of low density lipoprotein (LDL) is thought to play an important role in atherogenesis. Drugs of β-hydroxy-β-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) family are usually used as a very effective lipid-lowering preparations but they simultaneously block biosynthesis of both cholesterol and ubiquinone Q10 (coenzyme Q), which is an intermediate electron carrier in the mitochondrial respiratory chain. It is known that reduced form of ubiquinone Q10 acts in the human LDL as very effective natural antioxidant. Daily per os administration of HMG-CoA reductase inhibitor simvastatin to rats for 30 day had no effect on high-energy phosphates (adenosin triphosphate, creatine phosphate) content in liver but decreased a level of these substances in myocardium. We study the Cu2+-mediated susceptibility of human LDL to oxidation and the levels of free radical products of LDL lipoperoxidation in LDL particles from patients with atherosclerosis after 3 months treatment with natural antioxidants vitamin E as well as during 6 months administration of HMG-CoA reductase inhibitors such as pravastatin and cerivastatin in monotherapy and in combination with natural antioxidant ubiquinone Q10 or synthetic antioxidant probucol in a double-blind placebo-controlled trials. The 3 months of natural antioxidant vitamin E administration (400 mg daily) to patients did not increase the susceptibility of LDL to oxidation. On the other hand, synthetic antioxidant probucol during long-time period of treatment (3-6 months) in low-dose (250 mg daily) doesn’t change the lipid metabolism parameters in the blood of patients but their high antioxidant activity was observed. Really, after oxidation of probucol-contained LDL by C-15 animal lipoxygenase in these particles we identified the electron spin resonance signal of probucol phenoxyl radical that suggests the interaction of LDL-associated probucol with lipid radicals in vivo. We observed that 6 months treatment of patients with pravastatine (40 mg daily) or cerivastatin (0.4 mg daily) was followed by sufficiently accumulation of LDL lipoperoxides in vivo. In contrast, the 6 months therapy with pravastatin in combination with ubiquinone Q10 (60 mg daily) sharply decreased the LDL initial lipoperoxides level whereas during treatment with cerivastatin in combination with probucol (250 mg daily) the LDL lipoperoxides concentration was maintained on an invariable level. Therefore, antioxidants may be very effective in the prevention of atherogenic oxidative modification of LDL during HMG-CoA reductase inhibitors therapy. (Mol Cell Biochem 249: 129–140, 2003)

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
eBook
USD 16.99
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 16.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Steinberg D, Witztum JL: Lipoproteins and atherogenesis — current concepts. JAMA 264: 3047–3052, 1990

    Article  PubMed  CAS  Google Scholar 

  2. Davignon J, Laaksonen R: Low-density lipoprotein-independent effects of statins. Curr Opin Lipidol 10: 543–559, 1999

    Article  PubMed  CAS  Google Scholar 

  3. Gibbons GF, Mitropoulos KA, Myant NB: In: Biochemistry of Cholesterol. Biomedical Press, Amsterdam, 1982, pp 109–130

    Google Scholar 

  4. Folkers K, Langsjoen P, Willis R, Richardson P, Xia LJ, Ye CQ, Tamagawa H: Lovastatin decreases coenzyme Q levels in humans. Proc Natl Acad Sci USA 87: 8931–8934, 1990

    Article  PubMed  CAS  Google Scholar 

  5. 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 57: 62–66, 1995

    Article  PubMed  CAS  Google Scholar 

  6. Martinez-Garcia FA, Martin-Fernandez J, Molto JM, Villaverde R, Morales A, Fernandez-Barreiro A: Myopathy caused by inhibitors of hydroxymethylglutaryl-coenzyme A reductase. Rev Neurol 25: 869–871, 1997

    PubMed  CAS  Google Scholar 

  7. Steinberg D: Role of oxidized LDL and antioxidants in atherosclerosis. In: J.B. Longenecker et al. (eds). Nutrition and Biotechnology in Heart Disease and Cancer. Plenum Press, New York, 1995, pp 39–48

    Chapter  Google Scholar 

  8. Stocker R, Bowry VW, Frei B: Ubiquinol-10 protect human low density lipoprotein more efficiently against lipid peroxidation than does α-tocopherol. Proc Natl Acad Sci USA 88: 1646–1650, 1991

    Article  PubMed  CAS  Google Scholar 

  9. Cadenas E: Mechanisms of oxygen activation and reactive oxygen species detoxification. In: S. Ahmad (ed). Oxidative Stress and Antioxidant Defenses in Biology. Chapman and Hall, New York, 1995, pp 1–61

    Chapter  Google Scholar 

  10. Arrigoni O, Dipierro S, Borraccino G: Ascorbate free radical reductase, a key enzyme of the ascorbic acid system. FEBS Lett 125: 242–244, 1981

    Article  CAS  Google Scholar 

  11. Maellaro E, Del Bello B, Sugherini L, Santucci A, Comporti M, Casini AF: Purification and characterization of glutathione-dependent dehydroascorbate reductase from rat liver. Biochem J 301: 471–476, 1994

    PubMed  CAS  Google Scholar 

  12. Del Bello B, Maellaro E, Sugherini L, Santucci A, Comporti M, Casini AF: Purification of NADPH-dependent dehydroascorbate reductase from rat liver and its identification with 3a-hydroxysteroid dehydrogenase. Biochem J 304: 385–390, 1994

    Google Scholar 

  13. Mortensen S, Leth A, Agner E, Rohde M: Dose-related decrease of serum coenzyme Q-10 during treatment with HMG-CoA reductase inhibitors. Mol Aspects Med 18: S137–S144, 1997

    Article  PubMed  CAS  Google Scholar 

  14. Palomaki A, Malminiemi K, Sovakivi T, Malminiemi O: Ubiquinone supplementation during lovastatin treatment: Effect on LDL oxidation ex vivo. J Lipid Res 39: 1430–1437, 1998

    PubMed  CAS  Google Scholar 

  15. Lamprecht W, Stein P, Henz F, Weisser H: Creatine phosphate determination with creatine kinase, hexokinase, and glucose-6-phosphate dehydrogenase. In: H.U. Bergmeyer (ed). Methods of Enzymatic Analysis, vol. 4. Academic Press, New York, 1974, pp 1777–1781

    Chapter  Google Scholar 

  16. Pisarenko OI, Tskitishvily OV, Studneva IM, Serebryakova LI, Korchazhkina OV: Metabolic effects of ischemie preconditioning and adenosine receptor blockade in dogs. Ann NY Acad Sci 793: 85–97, 1996

    Article  PubMed  CAS  Google Scholar 

  17. Reimer KA, Hill ML, Jennings RB: Prolonged depletion of ATP and of adenine nucleotide pool due to delayed resynthesis of adenine nucleotides following reversible myocardial ischemie injury in dogs. J Mol Cell Cardiol 13: 229–239, 1981

    Article  PubMed  CAS  Google Scholar 

  18. Tertov VV, Kaplun VV, Dvoryantsev SN, Orekhov AN: Apolipoprotein B-bound lipids as a marker for evaluation of low density lipoprotein oxidation in vivo. Biochem Biophys Res Commun 214: 608–613, 1995

    Article  PubMed  CAS  Google Scholar 

  19. Lindgren RF: Preparative ultracentrifugal laboratory procedure suggestions for lipoprotein analysis. In: E.G. Perkins (ed). Analysis of Lipids and Lipoproteins. American Oil Chemical Society, New York, 1975, pp 204–224

    Google Scholar 

  20. Tikhaze AK, Lankin VZ, Kolycheva SN, Konovalova GG, Shumaev KB, Kozachenko AI, Gurevich SM, Zharova EA, Smirnov LD: Does trimetazidine act as antioxidant? Bull Exp Biol Med 126: 1132–1134, 1998

    Article  CAS  Google Scholar 

  21. Lankin VZ, Gordeeva NT, Osis YuG, Vikhert AM, Schewe T, Rapoport SM: Animal lipoxygenases: Change in activity of lipoxygenase from reticulocytes upon interaction with blood plasma lipoproteins. Biochemistry (Moscow) 48: 782–788, 1983

    Google Scholar 

  22. Lankin VZ, Kuhn H, Hiebsch C, Schewe T, Rapoport S, Tikhaze AK, Gordeeva NT: On the nature of the stimulation of the lipoxygenase from rabbit reticulocytes by biological membranes. Biomed Biochim Acta 44: 655–664, 1985

    PubMed  CAS  Google Scholar 

  23. Shumaev KB, Ruuge EK, Dmitrovsky AA, Bykhovsky VYa, Kukharchuk VV: Effect of lipid peroxidation products and antioxidants on the formation of probucol radical in low density lipoproteins. Biochemistry (Moscow) 62: 657–660, 1997.

    CAS  Google Scholar 

  24. Nourooz-Zadeh J, Tajaddini-Sarmadi J, Wolf SP: Measurement of plasma hydroperoxide concentrations by the ferrous oxidation — xylenol orange assay in conjunction with triphenylphosphine. Analyt Biochem 220: 403–409, 1994

    Article  PubMed  CAS  Google Scholar 

  25. Tikhaze AK, Lankin VZ, Konovalova GG, Shumaev KB, Kaminnyi AI, Kozachenko AI, Gurevich SM, Nagler LG, Zaitseva TM, Kukharchuk VV: Antioxidant probucol as an effective scavenger of lipid radicals in low density lipoproteins in vivo and in vitro. Bull Exp Biol Med 128: 818–821, 1999

    Article  CAS  Google Scholar 

  26. Kuzuya M, Kuzuya F: Probucol as an antioxidant and antiatherogenic drug. Free Radic Biol Med 14: 67–77, 1993

    Article  PubMed  CAS  Google Scholar 

  27. Cristol LS, Jialal I, Grundy SM: Effect of low-dose probucol therapy on LDL oxidation and the plasma lipoprotein profile in male volunteers. Atherosclerosis 97: 11–20, 1992

    Article  PubMed  CAS  Google Scholar 

  28. Dujovne CA, Harris WS, Gerrond LLC: Comparison of effects of probucol vs. vitamin E on ex vivo oxidation susceptibility of lipoproteins in hyperlipoproteinemia. Am J Cardiol 74: 38–42, 1994

    Article  PubMed  CAS  Google Scholar 

  29. Rodes J, Cote G, Lesperance J, Bourassa M, Doucet S, Bilodeau L, Bertrand OF, Hagel F, Gallo R, Tardif JC: Prevention of restenosis after angioplasty in small coronary arteries with probucol. Circulation 97: 429–436, 1998

    Article  PubMed  CAS  Google Scholar 

  30. Dujovne CA: New lowering drugs and new effects of old drugs. Curr Opin Lipidol 8: 362–368, 1997

    Article  PubMed  CAS  Google Scholar 

  31. Lankin VZ, Tikhaze AK, Kotelevtseva NV: Lipid peroxides and atherosclerosis. Kardiologiia (Cardiology) 16: 23–30, 1976 [Article in Russian; abstract in English]

    CAS  Google Scholar 

  32. Lankin VZ: Lipid peroxides and atherosclerosis. Hypothesis: The role of cholesterol and free radical lipid peroxidation in altering cell membrane properties during hypercholesterolemia and atherosclerosis. Kardiologiia (Cardiology) 20: 42–48, 1980 [Article in Russian; abstract in English]

    CAS  Google Scholar 

  33. Lankin VZ: Atherosclerosis as a free radical pathology. Excerpta Med (Int Congr Ser) G98: 385–388, 1992

    Google Scholar 

  34. Lankin VZ: Free radical lipoperoxidation during atherosclerosis. Free Radic Biol Med 16: 8, 1994

    Article  Google Scholar 

  35. Belkner J, Wiesner R, Kuhn H, Lankin VZ: The oxygenation of cholesterol esters by the reticulocyte lipoxygenase. FEBS Lett 279: 110–114, 1991

    Article  PubMed  CAS  Google Scholar 

  36. Kuhn H, Belkner J, Wiesner R, Schewe T, Lankin VZ, Tikhaze AK: Structure elucidation of oxygenated lipids in human atherosclerotic lesions. Eicosanoids 5: 17–22, 1992

    PubMed  CAS  Google Scholar 

  37. Lankin VZ, Vikhert AM, Kosykh VA, Tikhaze AK, Galakhov IE, Orekhov AN, Repin VN: Enzymatic detoxication of Superoxide anionradical and lipoperoxides in intima and media of atherosclerotic aorta. Biomed Biochim Acta 43: 797–802, 1984

    PubMed  CAS  Google Scholar 

  38. Osis YuG, Formaziuk VE, Lankin VZ, Dudina EI, Vikhert AM, Vladimirov YuA: The chemiluminescence of different classes lipoproteins from human blood serum. Vopr Med Khim (Problems of Medical Chemistry) 28: 122–126, 1982 [Article in Russian; abstract in English]

    CAS  Google Scholar 

  39. Wills RA, Folkers K, Lan Tucker J, Chun-Qu Y, Li-Jun X, Tamagawa H: Lovastatin decreases coenzyme Q levels in rats. Proc Natl Acad Sci USA 87: 8928–8930, 1990

    Article  Google Scholar 

  40. Tikhaze AK, Lankin VZ, Mikhin VP, Revenko VM, Lupanov VP: The antioxidant probucol as a regulator of the intensity of free radical lipid peroxidation processes in the blood of patients with coronary atherosclerosis. Ter. Arkh. (Therapeutic Archive) 69: 35–41, 1997 [Article in Russian; abstract in English]

    CAS  Google Scholar 

  41. Kumar D, Palace V, Danelisen I, Jugdutt BI, Singal PK: Probucol induced antioxidant confers protection against ischemia-reperfusion injury. J Mol Cell Cardiol. 33: A62, 2001

    Google Scholar 

  42. Lankin VZ, Tikhaze AK,.Konovalova GG, Kukharchuk VV: HMG-CoA reductase inhibitors induced the LDL oxidation. J Mol Cell Cardiol 33: A65, 2001

    Article  Google Scholar 

  43. Mannuel y Kennoy B, Vertommen J, Vinckx M, De Leeuw L: Effects of atorvastatin and and vitamin E on lipid peroxidation in patients with type I diabetes melitus. In: Abstr. Book Int. Conf. ‘Free Radicals, Nitric Oxide, and Inflammation: Molecular, Biochemical, and Clinical Aspects’. NATO-ASI, Anthalya (Turkey), 2001, p 83

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Cardiology Research Complex, Miasnikov’s Institute of Clinical Cardiocogy, Russia

    Vadim Z. Lankin, Alla K. Tikhaze, Valery V. Kukharchuk, Galina G. Konovalova, Alexander I. Kaminnyi, Konstantin B. Shumaev & Yury N. Belenkov

  2. Institute of Experimental Cardiology, 3rd Cherepkovaskaya, Moscow, Russia

    Oleg I. Pisarenko

Authors
  1. Vadim Z. Lankin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alla K. Tikhaze
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Valery V. Kukharchuk
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Galina G. Konovalova
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Oleg I. Pisarenko
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Alexander I. Kaminnyi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Konstantin B. Shumaev
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yury N. Belenkov
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Division of Stroke Vascular Disease, St. Boniface General Hospital Research Center, 351 Tache Avenue, R2H 2A6, Winnipeg, Manitoba, Canada

    James S. C. Gilchrist

  2. Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Center, 351 Tache Avenue, R2H 2A6, Winnipeg, Manitoba, Canada

    Paramjit S. Tappia  & Thomas Netticadan  & 

Rights and permissions

Reprints and permissions

Copyright information

© 2003 Springer Science+Business Media New York

About this chapter

Cite this chapter

Lankin, V.Z. et al. (2003). Antioxidants decreases the intensification of low density lipoprotein in vivo peroxidation during therapy with statins. In: Gilchrist, J.S.C., Tappia, P.S., Netticadan, T. (eds) Biochemistry of Diabetes and Atherosclerosis. Developments in Molecular and Cellular Biochemistry, vol 42. Springer, Boston, MA. https://doi.org/10.1007/978-1-4419-9236-9_17

Download citation

  • DOI: https://doi.org/10.1007/978-1-4419-9236-9_17

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4613-4852-8

  • Online ISBN: 978-1-4419-9236-9

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation