The Influence of Oxidative Stress, Carcinogens and Cloning on DNA ...

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Introduction Finally, flavo- <strong>and</strong> heme proteins, involved in the cellular energy processes, give rise to ROS derived from molecular oxygen after leak <strong>of</strong> electrons (197) . - Exogenous ROS ROS are exogenously introduced by exposure to environmental contaminants like transition metals, oxidants <strong>and</strong> free radicals or exposure to other forms <strong>of</strong> pollutants. Lifestyle factors (234) , ultraviolet light (UV) (235) , ionising radiations (236) , chemotherapeutic agents (237) , psycho- logical stress (238) are the major source to produce oxidants. Not only a negative lifestyle, like smoking is as a promoter for oxidative stress but also a positive habit can be causative as well. During muscular exercise, the requirement <strong>of</strong> the body for O2 is increased to fulfil the energy dem<strong>and</strong>s <strong>of</strong> this physical activity. Oxygen undergoes a four-electron transfer reaction producing ROS. Although it is highly recommended to perform muscular exercises to improve a healthy life because the produced ROS are beneficially used by the immune system <strong>and</strong> enhance its activity, the excess <strong>of</strong> exercises reveal serious adverse effects (239) . Surprisingly, it was concluded that intense long duration exercises reduce the immune function (240) <strong>and</strong> are associated with high frequency <strong>of</strong> other diseases as arteriosclerosis, cancer <strong>and</strong> premature ageing (241-243) . In contrast, both acute exhaustive <strong>and</strong> prolonged moderate exercises are usually related to the low risk <strong>of</strong> development <strong>of</strong> oxidative DNA dam- age signs <strong>and</strong> related diseases (244) . <strong>The</strong>se conflicts had attracted Poulsen et al. (245) to frame the relation between exercise <strong>and</strong> oxidative DNA modifications. <strong>The</strong> exposure to ionizing radiations <strong>and</strong> UV light increases the frequency <strong>of</strong> oxidative stress. <strong>The</strong> tropospheric ozone, found close to the ground, is created through the interactions <strong>of</strong> volatile organic compounds (VOCs) <strong>and</strong> nitrogen oxides in the presence <strong>of</strong> heat <strong>and</strong> sunlight producing harmful health effects. An increased level <strong>of</strong> oxygen free radical (specially 8-hydroxy- 2’-deoxyguanosine: 8-OH-dG) was recorded in ozone-exposed plants (246, 247) , explaining the mechanism <strong>of</strong> ozone-mediated plant injury. Although chemotherapy (anthracyclines, cyclophosphamide, cisplatin, cytarabine, mitomycin, fluorouracil <strong>and</strong> bleomycin) help in the improvement <strong>of</strong> the health <strong>of</strong> cancer patients, oxidative stress–mediated injury <strong>of</strong> normal tissues is a significant side effect. Some chemotherapeutic agents, such as bleomycin (248) , introduce oxidative stress as a mechanism to kill cancer cells. However, other chemotherapeutic agents, such as the anthracyclines (249, 250) , are more harmful by inducing oxidative stress in non- targeted tissues. 22
1.3.2.2 8-oxoguanosine 23 Introduction Among DNA oxidation, one <strong>of</strong> the most commonly occurred is the hydroxylation <strong>of</strong> guanine in the 8-position <strong>and</strong> formation <strong>of</strong> 7,8-dihydro-8-oxoguanosine (225) . This oxo-adduct gives rise to the most frequent somatic mutation found in human cancers (251) <strong>and</strong> described by lacking <strong>of</strong> base pairing <strong>and</strong> misreading <strong>of</strong> the modified base, whereas 8-OH-dG can pair with C or A. G:C → T:A is a transversion pathway (Fig. 10) which occurs <strong>of</strong>ten in association with the existence <strong>of</strong> 8-OH-dG adduct in vivo <strong>and</strong> in vitro <strong>and</strong> is confirming the diversity <strong>of</strong> the mutation forms detected with oxidative stress (252) . In most cases, oxidative stress is detected in parallel with aging, cancer <strong>and</strong> other related neurodegenerative diseases (251, 253-255) with rele- vant level <strong>of</strong> this adduct. Additionally, increased level <strong>of</strong> 8-OH-dG had been found in different pathological conditions as hepatitis, cardiovascular diseases, skin disorders, breast, lung <strong>and</strong> colon cancers (208) . From another side, the detection <strong>of</strong> 8-OH-dG in urine reflects the oxidative stress case (256) as well as the possible repair by a cellular N-glycolase (257) . <strong>The</strong>refore, it is the most <strong>of</strong>ten studied oxidative species as a marker for human biomonitoring <strong>of</strong> carcino- genesis (163, 234, 253, 258) . Figure 10: Mutation by 8-oxoguanosine 1.3.2.3 Methods <strong>of</strong> analysis <strong>of</strong> 8-oxoguanosine 5‘ 5‘ 5‘ 5‘ C G C oxoG A oxoG A T Determination <strong>of</strong> 8-OH-dG levels in DNA is <strong>of</strong> vital importance <strong>and</strong> requires a sensitive detection system due to its presence in nanomolar concentration range. Various methods are described for the detection <strong>and</strong> quantification <strong>of</strong> 8-OH-dG, such as high performance liquid ROS Replication Replication 5‘ 5‘ 5‘ 5‘
Page 1 and 2: The Influe
Page 3 and 4: The work at h<stro
Page 5 and 6: First, I feel always grateful to Al
Page 7: I would like to extend my thanks to
Page 11 and 12: The following acro
Page 13 and 14: FDA Food and drug
Page 15: RIA Radioimmunoassay ROS Reactive o
Page 18 and 19: Index 3.1 Spectrophotometeric deter
Page 20 and 21: Index 5.2.4.2 Dialysis of</
Page 22 and 23: Introduction 1.1.2 DNA methylation
Page 24 and 25: Introduction 1.2 The</stron
Page 26 and 27: Introduction Figure 4: Model for me
Page 28 and 29: Introduction Cancer is classified i
Page 30 and 31: Introduction DNA methylation Gene h
Page 32 and 33: Introduction 1.2.7.1 Clonin
Page 34 and 35: Introduction 1.2.8 Twins an
Page 36 and 37: Introduction chemicals, alkylating
Page 38 and 39: Introduction AP sites are not only
Page 40 and 41: Introduction 1.3.2.1 Oxidat
Page 44 and 45: Introduction chromatography with el
Page 46 and 47: Introduction One of</strong
Page 48 and 49: Introduction facturing of</
Page 50 and 51: Introduction 320) ; but due to its
Page 52 and 53: Introduction HO O O Figure 15: Mech
Page 54 and 55: Introduction - Methylation Sensitiv
Page 56 and 57: Introduction 5‘ 5‘ 5 Figure 18:
Page 58 and 59: Introduction - Radioactive-mediated
Page 60 and 61: Aim and objectives
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Results and Discus
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Results and Discus
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Summary 4 Summary DNA methylation i
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Summary The same s
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Experimental part Sodium tetrapheny
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Experimental part � Sodium tetrab
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Experimental part framework was fas
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Experimental part propanol
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Experimental part 12.5 mU/µL SPD)
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Experimental part Condition Value D
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Experimental part 5.4 Instrumentati
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Experimental part Graduated cylinde
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Experimental part 3-Nitrobenzanthro
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Appendix In-vitro: Denoting a react
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Appendix Laboratory Document Hydrol
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Appendix BODIPY and</strong
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Appendix Description of</st
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Appendix Transmission [%] 120 100 8
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Appendix Figure 62: Mass spectrum E
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List of figures Fi
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List of tables 8 L
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Literature Literature 1. Egger, G.;
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Literature 41. Bestor, T.H.; "<stro
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Literature 78. Venitt, S.; "Mechani
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Literature 113. Sinclair, K.D.; Mce
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Literature 148. Kadan-Lottick, N.S.
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Literature cyte DNA by gas chromato
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Literature 221. Mirand</str
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Literature 257. Lingaraju, G.M.; Sa
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Literature different tissues <stron
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Literature 324. Vishwanath, B.S.; F
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Literature 359. Wei, L.; Li, R.K.;
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Literature 394. Ramsahoye, B.H.; "M
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Literature 431. Wirtz, M.; Schumann
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Literature 467. Cornelius, M.; Wort
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Literature 502. Issa, J.P.J.; Ottav
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Literature 536. Pinheiro, J. <stron
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