Export file:


  • RIS(for EndNote,Reference Manager,ProCite)
  • BibTex
  • Text


  • Citation Only
  • Citation and Abstract

Free-radicals and advanced chemistries involved in cell membrane organization influence oxygen diffusion and pathology treatment

1 Biomaterials, SDB 539, 1919 7th Avenue South, University of Alabama at Birmingham, Birmingham, AL 35294, USA
2 Biomedical Research Technologies, 3830 Avenida Del Presidente, M/S 36, San Clemente, CA, 92674, USA

A breakthrough has been discovered in pathology chemistry related to increasing molecular structure that can interfere with oxygen diffusion through cell membranes. Free radicals can crosslink unsaturated low-viscosity fatty acid oils by chain-growth polymerization into more viscous liquids and even solids. Free radicals are released by mitochondria in response to intermittent hypoxia that can increase membrane molecular organization to reduce fluidity and oxygen diffusion in a possible continuing vicious cycle toward pathological disease. Alternate computational chemistry demonstrates molecular bond dynamics in free energy for cell membrane physiologic movements. Paired electrons in oxygen and nitrogen atoms require that oxygen bonds rotate and nitrogen bonds invert to seek polar nano-environments and hide from nonpolar nano-environments thus creating fluctuating instability at a nonpolar membrane and polar biologic fluid interface. Subsequent mechanomolecular movements provide free energy to increase diffusion by membrane transport of molecules and oxygen into the cell, cell-membrane signaling/recognition/defense in addition to protein movements for enzyme mixing. In other chemistry calcium bonds to membrane phosphates primarily on the outer plasma cell membrane surface to influence the membrane firing threshold for excitability and better seal out water permeation. Because calcium is an excellent metal conductor and membrane phosphate headgroups form a semiconductor at the biologic fluid interface, excess electrons released by mitochondria may have more broad dissipation potential by safe conduction through calcium atomic-sized circuits on the outer membrane surface. Regarding medical conditions, free radicals are known to produce pathology especially in age-related disease in addition to aging. Because cancer cell membranes develop extreme polymorphism that has been extensively followed in research, accentuated easily-visualized free-radical models are developed. In terms of treatment, use of vitamin nutrient supplements purported to be antioxidants that remove free radicals has not proved worthwhile in clinical trials presumably due to errors with early antioxidant measurements based on inaccurate colorimetry tests. However, newer covalent-bond shrinkage tests now provide accurate measurements for free-radical inhibitor hydroquinone and other molecules toward drug therapy.
  Article Metrics


1. Petersen R (2012) Reactive secondary sequence oxidative pathology polymer model and antioxidant tests, Int Res J Pure Appl Chem 2: 247–285.

2. Singer S, Nicolson G (1972) The fluid mosaic model of the structure of cell membranes. Science 175: 720–731.    

3. Nicolson G (2014) The fluid-mosaic model of membrane structure: still relevant to understanding the structure, function and dynamics of biological membranes after more than 40 years. Biochim Biophys Acta 1838: 1451–1466.    

4. Michael J, Sircar S, (2011) The Cell Membrane, In: Fundamentals of Medical Physiology, New York: Thieme Medical Publishers, 9–16.

5. Jeong M, Kang J (2008) Acrolein, the toxic endogenous aldehyde, induces neurofilament-L aggregation. BMB Rep 41: 635–639.    

6. Torosantucci R, Mozziconacci O, Sharov V, et al. (2012) Chemical modifications in aggregates of recombinant human insulin induced by metal-catalyzed oxidation: covalent crosslinking via Michael addition to tyrosine oxidation products. Pharm Res 29: 2276–2293.    

7. Rubenstein M, Leibler L, Bastide J (1992) Giant fluctuations of crosslink positions in gels. Phys Rev Lett 68: 405–407.    

8. Nossal R (1996) Mechanical properties of biological gels. Physica A 231: 265–276.    

9. Barsky S, Plischke M, Joos B, et al. (1996) Elastic properties of randomly cross-linked polymers Phys Rev E 54: 5370–5376.

10. Ulrich S, Zippelius A, Benetatos P (2010) Random networks of cross-linked directed polymers. Phys Rev E 81: 021802.

11. Rodriquez F, (1996) 11.3 Polymer degradation, In: Principles of Polymer Systems, 4 Eds., Washington D.C.: Taylor and Francis, 398–399.

12. Dröge W (2002) Free radicals in the physiological control of cell function. Physiol Rev 82: 47–95.

13. Valko M, Leibfritz D, Moncol J, et al. (2007) Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol 39: 44–84.    

14. Floyd R, Towner R, He T, et al. (2011) Translational research involving oxidative stress diseases of aging. Free Radic Biol Med 51: 931–941.    

15. Sena L, Chandel N ( 2012) Physiological roles of mitochondrial reactive oxygen species. Mol Cell 48: 158–167.

16. Labunskyy V, Gladyschev V (2013) Role of reactive oxygen species-mediated signaling in aging. Antioxid Redox Signal 19: 1362–1372.    

17. Hill S, Remmen H (2014) Mitochondrial stress signaling in longevity: a new role for mitochondrial function in aging. Redox Biol 2: 936–944.    

18. Schieber M, Chandel N (2014) ROS function in redox signaling and oxidative stress. Curr Biol 24: R453–R462.    

19. Girotti A (1998) Lipid hydroperoxide generation, turnover, and effector action in biological systems. J Lipid Res 39: 1529–1542.

20. Beckman K, Ames B (1998) The free radical theory of aging matures. Physiol Rev 78: 547–581.

21. Valko M, Rhodes C, Moncol, et al. (2006) Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem Biol Interac 160: 1–40.    

22. Silva J, Coutinho O (2010) Free radicals in the regulation of damage and cell death-basic mechanisms and prevention. Drug Discov Ther 4: 144–167.

23. Jacob K, Hooten N, Trzeciak A, et al. (2013) Markers of oxidant stress that are clinically relevant in aging and age-related disease. Mech Ageing Dev 134: 139–157.    

24. Phaniendra A, Jestadi D, Periyasamy L (2015) Free radicals: properties, sources, targets, and their implication in various diseases. Ind J Clin Biochem 30: 11–26.

25. Harman D (1956) Aging: a theory based on free radical and radiation chemistry. J Gerontol Soc 11: 298–300.    

26. Shigenaga M, Hagen T, Ames B (1994) Oxidative damage and mitochondrial decay in aging. Proc Natl Acad Sci USA 91: 10771–10778.    

27. Balaban R, Nemoto S, Finkel T (2005) Mitochondria, oxidants, and aging. Cell 120: 483–495.

28. Harman D (2006) Free radical theory of aging: an update. Ann NY Acad Sci 1067: 10–21.    

29. Colavitti R, Finkel T (2005) Reactive oxygen species as mediators of cellular senescence. IUBMB Life 57: 277–281.    

30. Ziegler D, Wiley C, Velarde M (2015) Mitochondrial effectors of cellular senescence: beyond the free radical theory of aging. Aging Cell 14: 1–7.    

31. Eichenberger K, Böhni P, Wintehalter K, et al. (1982) Microsomal lipid peroxidation causes an increase in the order of the membrane lipid domain. FEBS Letters 142: 59–62.    

32. Kaplán P, Doval M, Majerová Z, et al. (2000) Iron-induced lipid peroxidation and protein modification in endoplasmic reticulum membranes. Protection by stobadine. Int J Biochem Cell Biol 32: 539–547.    

33. Solans R, Motta C, Solá R, et al. (2000) Abnormalities of erythrocyte membrane fluidity, lipid composition, and lipid peroxidation in systemic sclerosis. Arthritis Rheum 43: 894–900.    

34. Pretorius E, Plooy J, Soma P, et al. (2013) Smoking and fluidity of erythrocyte membranes: a high resolution scanning electron and atomic force microscopy investigation. Nitric Oxide 35: 42–46.    

35. de la Haba C, Palacio J, Martínez P, et al. (2013) Effect of oxidative stress on plasma membrane fluidity of THP-1 induced macrophages. Biochim Biophys Acta 1828: 357–364.    

36. Alberts B, Johnson A, Lewis J, et al. (2002) The Lipid Bilayer, In: Molecular Biology of the Cell, 4 Eds., New York: Garland Science.

37. Weijers R (2012) Lipid composition of cell membranes and its relevance in type 2 diabetes mellitus. Curr Diabetes Rev 8: 390–400.    

38. Benderitter M, Vincent-Genod L, Pouget J, et al. (2003) The cell membrane as a biosensor of oxidative stress induced by radiation exposure: a multiparameter investigation. Radiat Res 159: 471–483.    

39. Zimniak P (2011) Relationship of electrophilic stress to aging. Free Radic Biol Med 51: 1087–1105.    

40. Wang S., Von Meerwall E, Wang SQ, et al. (2004). Diffusion and rheology of binary polymer mixtures. Macromolecules 37: 1641–1651.    

41. Williams R (1989) NMR studies of mobility within protein structure. Euro J Biochem 183: 479–497.

42. Sapienza, P, Lee A (2010) Using NMR to study fast dynamics in proteins: methods and applications. Curr Opin Pharmacol 10: 723–730.

43. Petersen R (2014) Computational conformational antimicrobial analysis developing mechanomolecular theory for polymer biomaterials in materials science and engineering. Int J Comput Mater Sci Eng 3: 145003.

44. Goldstein D, (1990) Chapter 143 Serum Calcium, In: Walker H, Hall W, Hurst J, Editors, Clinical Methods: The History, Physical, and Laboratory Examinations, 3 Eds., Boston: Butterworths.

45. Tung IC (1991) Application of factorial design to SMC viscosity build-up. Polym Bull 25: 603–610.

46. Peters S, (1998) Particulate Fillers, In: Handbook of Composites, 2 Eds., New York: Chapman & Hall, 242–243.

47. Gaucheron F (2005) The minerals of milk. Reprod Nutr Dev 45: 473–483.    

48. Komabayashi T, Zhu Q, Eberhart R, et al. (2016) Current status of direct pulp-capping materials for permanent teeth. Dent Mater J 35: 1–12.

49. Petersen R, Vaidya U, (2011) Chapter 16 Free Radical Reactive Secondary Sequence Lipid Chain-Lengthening Pathologies, In: Micromechanics/Electron Interactions for Advanced Biomedical Research, Saarbrücken: LAP LAMBERT Academic Publishing Gmbh & Co. KG., 233–287.

50. McMurry J, (2004) Organic Chemistry 6 Eds, Belmont, CA: Thompson Brooks/Cole., 136–138.

51. Esterbauer H, Schaur R, Zollner H (1991) Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes. Free Radic Biol Med 11: 81–128.    

52. Lovell M, Xie C, Markesbery W (2000) Acrolein, a product of lipid peroxidation, inhibits glucose and glutamate uptake in primary neuronal cultures. Free Radic Biol Med 29: 714–720.    

53. Shi R, Rickett T, Sun W (2011) Acrolein-mediated injury in nervous system trauma and diseases. Mol Nutr Food Res 55: 1320–1331.    

54. Uchida K (1999) Current status of acrolein as a lipid peroxidation product. Trends Cardiovasc Med 9: 109–113.    

55. Minko I, Kozekov I, Harris T, et al. (2009) Chemistry and biology of DNA containing 1,N2-deoxyguanosine adducts of the α,β-unsaturated aldehydes acrolein, crotonaldehyde, and 4-hydroxynonenal. Chem Res Toxicol 22: 759–778.    

56. Singh M, Kapoor A, Bhatnagar A (2014) Oxidative and reductive metabolism of lipid-peroxidation derived carbonyls. Chem Biol Interact 234: 261–273.

57. Ishii T, Yamada T, Mori T, et al. (2007) Characterization of acrolein-induced protein cross-links. Free Radic Res 41: 1253–1260.    

58. Michael J, Sircar S, (2011) Electrophysiology of Ion Channels, In: Fundamentals of Medical Physiology, New York: Thieme Medical Publishers, 43–46.

59. Han P, Trinidad B, Shi J (2015) Hypocalcemia-induced seizure: demystifying the calcium paradox. ASN Neuro 7: 1–9.

60. Parekh A, Putney J (2005) Store-operated calcium channels. Physiol Rev 85: 757–810.    

61. Sherwood L, (2004) Endocrine Control of Calcium Metabolism, In: Human Physiology, 5 Eds., Belmont, CA: Thomson-Brooks/Cole, 733–742.

62. Michael J, Sircar S, (2011) Mechanisms to Regulate Whole Body pH, In: Fundamentals of Medical Physiology, New York: Thieme Medical Publishers, 399–400.

63. Lide D, (1996) Electrical Resistivity of Pure Metals, In: Handbook of Chemistry and Physics, 77 Eds., New York: CRC Press, 12-40–12-41.

64. Jendrasiak G, Smith R (2004) The interaction of water with the phospholipid head group and its relationship to the lipid electrical conductivity. Chem Phys Lipids 131: 183–195.    

65. Petersen R (2011) Bisphenyl-polymer/carbon-fiber-reinforced composite compared to titanium alloy bone implant. Int J Polym Sci 2011: 2341–2348.

66. Callister W, (1997) Room Temperature Electrical Resistivity Values for Various Engineering Materials Table C.9, In: Materials Science and Engineering, New York: John Wiley & Sons, 796–798.

67. Park B, Lakes R, (1992) Characterization of Materials II Table 4.1, In: Biomaterials, 2 Eds., New York: Plenum Press, 64.

68. Halliday D, Resnick R, Walker J, (1993) 46-2 Electrical Conductivity, In: Fundamentals of Physics, 4 Eds., New York: JohnWiley & Son, 1210.

69. Periodic Table of the Elements (2016) Sulfur-Electrical Properties accessed November 10, 2016. Available from: http://www.periodictable.com/Elements/016/data.html.

70. Clandinin M, Cheema S, Field C, et al. (1991) Dietary fat: exogenous determination of membrane structure and cell function. FASEB J 5: 2761–2769.

71. McMurry J, (2004) Biomolecules: Lipids, In: Organic Chemistry, 6 Eds., Belmont, CA: Thompson Brooks/Cole, 1027–1033.

72. Sherwood L, (2004) Lipids, In: Human Physiology, 5 Eds., Belmont, CA: Thomson-Brooks/Cole, A12–A13.

73. Villaláın J, Mateo C, Aranda F, et al. (2001) Membranotropic effects of the antibacterial agent triclosan. Arch Biochem Biophys 390: 128–136.

74. Guillén J, Bernabeu A, Shapiro S, et al. (2004) Location and orientation of Triclosan in phospholipid model membranes. Eur Biophys J 33: 448–453.

75. Alberts B, Johnson A, Lewis J, et al. (2002) Electron-Transport Chains and Their Proton Pumps, In: Molecular Biology of the Cell, 4 Eds., New York: Garland Science.

76. Sherwood L, (2004) Acid-Base Balance, In: Human Physiology, 5 Eds., Belmont, CA: Thomson-Brooks/Cole, 571–577.

77. Hüttemann M, Lee I, Grossman L, et al. (2012) Chapter X. phosphoylation of mammalian cytochrome c and cytochrome c oxidase in the regulation of cell destiny: respieration, apoptosis, and human disease. Adv Exp Med Biol 748: 237–264.

78. Srinivasan S, Avadhani N (2012) Cytochrome c oxidase dysfunction in oxidative stress. Free Radic Biol Med 53: 1252–1263.    

79. Finkel T, Holbrook N (2000) Oxidants, oxidative stress and the biology of ageing. Nature 408: 239–247.    

80. Brand M, Affourtit C, Esteves T, et al. (2004) Serial review: the powerhouse takes control of the cell: the role of mitochondria in signal transduction. Free Radic Biol Med 37: 755–767.    

81. Tosato M, Zamboni V, Ferrini A, et al (2007) The aging process and potential interventions to extend life expectancy. Clinical Interv Aging 2: 401–412.

82. Murphy M (2009) How mitochondria produce reactive oxygen species. Biochem J 417:1–13.    

83. Kagan V, Wipf P, Stoyanovsky D, et al. (2009) Mitochondrial targeting of electron scavenging antioxidants: regulation of selective oxidation vs random chain reactions. Adv Drug Deliv Rev 61: 1375–1385.    

84. Niizuma K, Yoshioka H, Chen H, et al. (2010) Mitochondrial and apoptotoc neuronal death signaling pathways in cerebral ischemia. Biochim Biophys Acta 1802: 92–99.    

85. Michael J, Sircar S, (2011) Metabolic Pathways, In: Fundamentals of Medical Physiology, New York: Thieme Medical Publishers, 467–468.

86. Halliwell B (1987) Oxidants and human disease: some new concepts. FASEB J 1: 358–364.

87. Petersen R (2013) Free-radical polymer science structural cancer model: a review. Scientifica 2013: 143589.

88. Alberts B, Johnson A, Lewis J, et al. (2002) Proteins Function, In: Molecular Biology of the Cell, 4 Eds., New York: Garland Science.

89. Reineri S, Bertoni A, Sanna E, et al. (2007) Membrane lipid rafts coordinate estrogen-dependent signaling in human platelets. Biochim Biophys Acta 1773: 273–278.    

90. Pamplona R, Portero-Otin M, Requena J, et al. (1999) A low degree of fatty acid unsaturation leads to lower lipid peroxidation and lipoxidation-derived protein modification in heart mitochondria of the longevous pigeon than in the short-lived rat. Mech Ageing Dev 106: 283–286.    

91. Wang Y, Cui P (2015) Reactive carbonyl species derived from omega-3 and omega-6 fatty acids. J Agric Food Chem 63: 6293–6296.    

92. National Cancer Institute/National Institutes of Health/Department of Health and Human Services (2006) What You Need To Know About Cancer Bethesda, MD: NIH.

93. Weinhouse S, Warburg O, Burk D, et al. (1956) On respiratory impairment in cancer cells. Science 124: 269–270.

94. Gillies R, (2001) The Tumour Microenvironment: Causes and Consequences of Hypoxia and Acidity, Novartis Foundation Symposium 240, New York: JohnWiley & Sons.

95. Stavridis J, (2008) Oxidation: the Cornerstone of Carcinogenesis, New York: Springer.

96. Grek C, Tew K (2010) Redox metabolism and malignancy. Current Opin Pharmacol 10: 362–368.    

97. Fogg V, Lanning N, MacKeigan J (2011) Mitochondria in cancer: at the crossroads of life and death. Chin J Cancer 30: 526–539.    

98. Hielscher A, Gerecht S (2015) Hypoxia and free radicals: role in tumor progression and the use of engineering-based platforms to address these relationships. Free Radic Biol Med 79: 281–291.    

99. Görlach A, Dimova E, Petry A, et al. (2015) Reactive oxygen species, nutrition, hypoxia and diseases: problems solved? Redox Biol 6: 372–385.    

100. Tafani M, Sansone L, Limana F, et al. (2016) The interplay of reactive oxygen species, hypoxia, inflammation, and sirtuins in caner initiation and progression. Oxid Med Cell Longev 2016: 1–18.

101. Peacock J, Calhoun A, (2006) Polymer Chemistry Properties and Applications, Munich, Germany: Hanser.

102. Mironi-Harpaz I, Narkis M, Siegmann A (2007) Peroxide crosslinking of a styrene-free unsaturated polyester. J Appl Polym Sci 105: 885–892.    

103. Wang Y, Woodworth L, Han B (2011) Simultaneous measurement of effective chemical shrinkage and modulus evolutions during polymerization. Exp Mech 51: 1155–1169.    

104. Jansen K, Vreugd de J, Ernst L (2012) Analytical estimate for curing-induced stress and warpage in coating layers. J Appl Polym Sci 126: 1623–1630.    

105. Weinberg R, (2007) 14.3 The epithelial-mesenchymal transition and associated loss of E-cadherin expression enable carcinoma cells to become invasive, In: The Biology of Cancer, New York: Garland Science, 597–624.

106. Wenger J, Chun S, Dang D, et al. (2011) Combination therapy targeting cancer metabolism. Med Hypotheses 76: 169–172.    

107. Vinogradova T, Miller P, Kaverina I (2009) Microtubule network asymmetry in motile cells: role of Golgi-derived array. Cell Cycle 8: 2168–2174.    

108. Lindberg U, Karlsson R, Lassing I, et al. (2008) The microfilament system and malignancy. Semin Cancer Biol 18: 2–11.    

109. San Martín A, Griendling K (2010) Redox control of vascular smooth muscle migration. Antioxid Redox Signal 12: 625–640.    

110. Copstead LE, Banasik J, (2005) Pathophysiology, 6 Eds., St. Louis, MO: Elsevier Saunders, 221.

111. Li Z, Hannigan M, Mo Z, et al. (2003) Directional Sensing Requires Gβγ-Mediated PAK1 and PIXα-Dependent Activation of Cdc42. Cell 114: 215–227.    

112. Hattori H, Subramanian K, Sakai J, et al. (2010) Small-molecule screen identifies reactive oxygen species as key regulators of neutrophile chemotaxis. PNAS 107: 3546–3551.    

113. Parisi F, Vidal M (2011) Epithelial delamination and migration: lessons from Drosophila. Cell Adh Migr 5: 366–372.    

114. Barth A, Caro-Gonzalez H, et al. (2008) Role of adenomatous polyposis coli (APC) and microtubules in directional cell migration and neuronal polarization. Semin Cell Dev Biol 19: 245–251.    

115. Dent E, Gupton S, et al. (2010) The growth cone cytoskeleton in axon outgrowth and guidance. Cold Spring Harb Perspect Biol 3: a001800.

116. Saraswathy S, Wu G, et al. (2006) Retinal microglial activation and chemotaxis by docosahexaenoic acid hydroperoxide. Invest Ophthalmol Vis Sci 47: 3656–3663.    

117. Dunlop R, Dean R, Rodgers K (2008) The impact of specific oxidized amino acids on protein turnover in J774 cells. Biochem J 410: 131–140.    

118. Darling E, Zauscher S, Block J (2007) A thin-layer model for viscoelastic, stress-relaxation testing of cells using atomic force microscopy: do cell properties reflect metastatic potential. Biophys J 92: 1784–1791.    

119. Fleischer F, Ananthakrishnan R, (2007) Actin network architecture and elasticity in lamellipodia of melanoma cells. New J Phys 9: 420.    

120. Pokorný J, Jandový A, Nedbalová (2012) Mitochondrial metabolism-neglected link of cancer transformation and treatment. Prague Med Rep 113: 81–94.

121. Qian Y, Luo J, Leonard S, et al. (2003) Hydrogen peroxide formation and actin filament reorganization by Cdc42 are essential for ethanol-induced in vitro angiogenesis. J Biol Chem 278: 16189–16197.    

122. Gawdzik B, Księzopolski J, Matynia T (2003) Synthesis of new free-radical initiators for polymerization. J Appl Polym Sci 87: 2238–2243.    

123. Miller Y, Worrall D, Funk C, et al. (2003) Actin polymerization in macrophages in response to oxidized LDL and apoptotic cells: role of 12/15-lipoxygenase and phosphoinositide 3-kinase. Mol Biol Cell 14: 4196–4206.    

124. Ushio-Fukai M, Nakamura Y (2008) Reactive oxygen species and angiogenesis: NADPH oxidase as target for cancer therapy. Cancer Lett 266: 37–52.    

125. Taparowsky E, Suard Y, Fasano O (1982) Activation of the T24 bladder carcinoma transforming gene is linked to a single amino acid change. Nature 300: 762–765.    

126. Swaminathan V, Mythreye K, Tim O'Brien E, et al. (2011) Mechanical Stiffness grades metastatic potential in patient tumor cells and in cancer cell lines. Cancer Res 71: 5075–5080.    

127. Xu W, Mezencev R, Kim B, et al. (2012) Cell stiffness is a biomarker of the metastatic potential of ovarian cancer cells. PLoS ONE 7: e46609.    

128. Hoyt K, Castaneda B, Zhang M, et al. (2008) Tissue elasticity properties as biomarkers for prostate cancer. Cancer Biomark 4: 213–225.    

129. Ghosh S, Kang T, Wang H, et al. (2011) Mechanical phenotype is important for stromal aromatase expression. Steroids 76: 797–801.    

130. Kraning-Rush C, Califano J, Reinhart-King C (2012) Cellular traction stresses increase with increasing metastatic potential. PLoS ONE 7: e32572.    

131. Trichet L, Le Digabel J, Hawkins R, et al. Evidence of a large-scale mechanosensing mechanism for cellular adaptation to substrate stiffness. Proc Natl Acad Sci U.S.A. 109: 6933–6938.

132. Peto R, Doll R, Buckley J (1981) Can dietary beta-carotene materially reduce human cancer rates? Nature 290: 201–208.    

133. Shike M, Winawer S, Greenwald P, et al. (1990) Primary prevention of colorectal cancer. Bull World Health Organ 68: 337–385.

134. Dorgan J, Schatzkin A (1991) Antioxidant micronutrients in cancer prevention. Hematol Oncol Clin North Am 5: 43–68.

135. Chlebowski R, Grosvenor M (1994) The scope of nutrition intervention trials with cancer-related endpoints. Cancer 74: 2734–2738.    

136. Ziegler R, Mayne S, Swanson C (1996) Nutrition and lung cancer. Cancer Causes Control 7: 157–177.    

137. Levander O (1997) Symposium: newly emerging viral diseases: what role for nutrition? J Nutr 127: 948S–950S.

138. Willett W (1999) Convergence of philosophy and science: the Third International Congress on Vegetarian Nutrition. Am J Clin Nutr 70(suppl): 434S–438S.

139. Meydani M (2000) Effect of functional food ingredients: vitamin E modulation of cardiovascular diseases and immune status in the elderly. Am J Clin Nutr 71(suppl): 1665S–1668S.

140. Simopoulos A (2001) The Mediterranean diets: what is so special about the diet of Greece? The scientific experience. J Nutr 131: 3065S–3073S.

141. Rock C, Demark-Wahnefried W (2002) Nutrition and survival after the diagnosis of breast cancer: a review of the evidence. J Clin Oncol 20: 3302–3316.    

142. Seifried H, McDonald S, Anderson D, et al. (2003) The antioxidant conundrum in cancer. Cancer Res 63: 4295–4298.

143. Männistö S, Smith-Warner S, Spiegelman D, et al. (2004) Dietary carotenoids and risk of lung cancer in a pooled analysis of seven cohort studies. Cancer Epidemiol Biomarkers Prev 13: 40–48.    

144. Fraga C (2007) Plant polyphenols: how to translate their in vitro antioxidant actions to in vivo conditions. Life 59: 308–315.

145. Kushi L, Doyle C, McCullough M, et al. (2012) American cancer society guidelines on nutrition and physical activity for cancer prevention. CA Cancer J Clin 62: 30–67.    

146. Heinonen O, Albanes D, Huttunen J, et al. (1994) The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med 330: 1029–1035.    

147. Hennekens C, Buring J, Manson J, et al. (1996) Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease. N Engl J Med 334: 1145–1149.    

148. Omenn G, Goodman G, Thornquist M, et al. (1996) Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med 334: 1150–1155.    

149. Albanes D (1999) β-carotene and lung cancer: a case study. Am J Clin Nutr 69(suppl): 1345S–1350S.

150. Virtamo J, Albanes D, Huttunen J, et al. (2003) Incidence of cancer and mortality following α-tocopherol and β-carotene supplementation. JAMA 290: 476–485.    

151. Sommer A, Vyas K (2012) A global clilnical view on vitamin A and carotenoids. Am J Clin Nutr 96(suppl): 1204–1206.

152. Thompson I, Kristal A, Platz E (2014) Prevention of prostate cancer: outcomes of clinical trails and future opportunities. Am Soc Clin Oncol Educ Book 2014: e76–e80.

153. Virtamo J, Taylor P, Kontto J, et al (2014) Effects of α-tocopherol and β-carotene supplementation on cancer incidence and mortality: 18-year post-intervention follow-up of the alpha-tocopherol, beta-carotene cancer prevention (ATBC) study. Int J Cancer 135: 178–185.    

154. Yusuf S, Phil D, Dagenais G, et al. (2000) Vitamin E supplementation and cardiovascular events in high-risk patients. N Engl J Med 342: 154–160.    

155. Devaraj S, Tang R, Adams-Huet B, et al. (2007) Effect of high-dose α-tocopherol supplementation on biomarkers of oxidative stress and inflammation and carotid atherosclerosis in patients with coronary artery disease. Am J Clin Nutr 86: 1392–1398.

156. Sesso H, Buring J, Christen W, et al (2008) Vitamins E and C in the prevention of cardiovascular disease in men. JAMA 300: 2123–2133.

157. Brigelius-Flohe R, Galli F (2010) Vitamin E: a vitamin still awaiting the detection of its biological function. Mol Nutr Food Res 54: 583–587.    

158. Schultz M, Leist M, Petrzika M, et al. (1995) Novel urinary metabolite of α-tocopherol, 2,5,7,8-tetramethyl-2(2'-carboxyethyl)-6-hydroxychroman, as an indicator of an adequate vitamin E supply. Am J Clin Nutr 62(suppl): 1527S–1534S.

159. Azzi A (2007) Molecular mechanism of α-tocopherol action. Free Radic Biol Med 43: 16–21.    

160. Boddupalli S, Mein J, Lakkanna S, et al. (2012) Induction of phase 2 antioxidant enzymes by broccoli sulforaphane: perspectives in maintaining the antioxidant activity of vitamins A, C, and E. Front Genet 3: 1–15.

161. Lü JM, Lin P, Yao Q, et al. (2010) Chemical and molecular mechanisms of antioxidants: experimental approaches and model systems. J Cell Mol Med 14: 840–860.    

162. Apak R, Güçlü K, Özyürek M, et al. (2008) Mechanism of antioxidant capacity assays and the CUPRAC (cupric ion reducing antioxidant capacity) assay. Microch Acta 160: 413–419.

163. Özyürek M, Bektaşoğlu B, Güçlü K, et al. (2008) Simultaneous total antioxidant capacity assay of lipohilic and hydrophilic antioxidants in the same acetone-water solution containing 2% methyl-β-cyclodextrin using the cupric reducing antioxidant capacity (CUPRAC) method. Anal Chim ACTA 630: 28–39.    

164. McMurry J, (2004) Organic Chemistry, 6 Eds., Belmont, CA: Thompson Brooks/Cole, 403–405, 482–483, 486–487.

165. Dumas D, Muller S, Gouin F, et al. (1997) Membrane fluidity and oxygen diffusion in cholesterol enriched erythrocyte membrane. Arch Biochem Biophys 341: 34–39.    

166. Cazzola R, Rondanelli M, Russo-Volpe S, et al. (2004) Decreased membrane fluidity and altered susceptibility to peroxidation and lipid composition in overweight and obese female erythrocytes. J Lipid Res 45: 1846–1851.    

167. Madmani M, Yusaf S, Tamr A, et al. (2014) Coenzyme Q10 for heart failure (Review). Cochrane Database Syst Rev 2014.

168. Watts G, Playford D, Croft K, et al. (2002). Coenzyme Q10 improves endothelial dysfunction of brachial artery in type II diabetes mellitus. Diabetologia 45:420–426.

169. DeCaprio A (1999) The toxicology of hydroquinone-relevance to occupational and environmental exposure. Crit Rev Toxicol 29: 283–330.    

170. McMurry J, (2004) 17.11 Reactions of Phenols, In: Organic Chemistry, 6 Eds., Belmont, CA: Thompson Brooks/Cole, 618–619.

171. Takata J, Matsunage K, Karube Y (2002) Delivery systems for antioxidant nutrients. Toxicology 180: 183–193.    

172. Pifer, J, Hearne F, Friedlander B, et al. (1986) Mortality study of men employed at a large chemical plant, 1972 through 1982. J Occup Med 28: 438–444.    

173. Pifer J, Hearne F, Swanson F (1995) Mortality study of employees engaged in the manufacture and use of hydroquinone. Int Arch Occup Environ Health 67: 267–280.    

174. Sterner J, Oglesby F, Anderson B (1947) Quinone vapors and their harmful effects. I Corneal and conjunctival injury. J Ind Hyg Toxicol 29: 60–73.

175. Carlson A, Brewer N (1953) Toxicity studies on hydroquinone. Proc Soc Exp Biol Med 84: 684–688.    

176. O'Donoghue J (2006) Hydroquinone and its analogues in dermatology-a risk-benefit viewpoint. J Cosmet Dermatol 5: 196–203.    

177. Nordlund J, Grimes P, Ortonne J (2006) The safety of hydroquinone. JEADV 20: 781–787.

178. Arndt K, Fitzpatrick T (1965) Topical use of hydroquinone as a depigmenting agent. JAMA 194: 965–967.    

179. Deisinger P, Hill T, English C (1996) Human exposure to naturally occurring hydroquinone. J Toxicol Env Health 47: 31–46.

180. Levitt J (2007) The safety of hydroquinone: a dermatologist's response to the 2006 Federal Register. J Am Acad Dermatol 57: 854–872.    

181. Marcus R, Sutin N (1985) Electron transfers in chemistry and biology. Biochim Biophys Acta 811: 265–322.    

182. Dumas D, Latger V, Viriot M-L, et al. (1999) Membrane fluidity and oxygen diffusion in cholesterol-enriched endothelial cells. Clin Hemorheol Microcirc 21: 255–261.

183. National Toxicology Program (1989) Toxicology and carcinogenesis studies of hydroquinone in F-344/N rats and B6C3F mice. NIH Publication : 90–2821.

184. Shibata MA, Hirose M, Tanaka H, et al. (1991) Induction of renal cell tumors in rats and mice, and enhancement of hepatocellular tumor development in mice after long-term hydroquinone treatment. Jap J Can Res 82: 1211–1219.    

185. Poet T, Wu H, English J, et al (2004) Metabolic rate constants for hydroquinone in F344 rat and human liver isolated hepatocytes: application to a PBPK model. Toxicol Sci 82: 9–25.    

186. MacDonald J (2004) Human carcinogenic risk evaluation, part IV: assessment of human risk of cancer from chemical exposure using a global weight-of-evidence approach. Toxicol Sci 82: 3–8.    

187. Food and Drug Administration (2015) Hydroquinone studies under the national toxicology program (NTP). 11/27/2015. Accessed 11/2016, Available from: http://www.fda/gov/About FDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm203112.htm.

Copyright Info: © 2017, Richard C Petersen, licensee AIMS Press. This is an open access article distributed under the terms of the Creative Commons Attribution Licese (http://creativecommons.org/licenses/by/4.0)

Download full text in PDF

Export Citation

Article outline

Show full outline
Copyright © AIMS Press All Rights Reserved