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

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Introduction facturing <strong>of</strong> rubbers <strong>and</strong> plastics <strong>and</strong> finally in dyes <strong>and</strong> paints industry. Among 19 structurally determined HAAs (290) , 4-Aminobiphenyl (4-ABP) is a major agent investigated for its role in the etiology <strong>of</strong> mainly bladder cancer (298, 299) <strong>and</strong> breast cancer (297, 300) . 4-ABP occurs in amounts <strong>of</strong> 0.2 <strong>and</strong> 140 ng per cigarette noting the formation <strong>of</strong> 4-ABP-hemoglobin adducts in smokers (301) . It is metabolically activated in a manner like 3-NBA by the cytochrome P450 (294) in liver to N-hydroxy-4 ABP which forms covalent DNA adduct <strong>and</strong> induce mutations at multiples sites ( 302) e.g. at the C8 position <strong>of</strong> guanine by their exocyclic amino group. <strong>The</strong> latter activated form enters the circulation <strong>and</strong> produce haemoglobin adducts or is further transported to urinary bladder to react either directly with DNA or after N-acetylation (Fig. 13). N-sulphation <strong>and</strong> N-glucorination are other reported metabolic activation pathways (303) . 4-ABP is also associated with cancer in the fatty sites in the human body as adipose tissue <strong>of</strong> breast due to its lipophilic nature via its activation by peroxidises enzymes in the mammary gl<strong>and</strong> following O-esterification pathway to produce adducts with DNA (304) (Fig. 13). N-hydroxylation [P-450] Liver 4-ABP N-OH-4-ABP Peroxidase enzymes (LPO) Reactive nitrinium cation Or other oxidised intermediates DNA Adducts Breast cancer NH 2 N Transportation to urinary bladder N-OH-4-Acetyl-ABP Bladder cancer N-acetyltransferase Figure 13: Proposed metabolic activation pathway <strong>of</strong> 4-ABP 28 NOCOCH 3 Blood Circulation Osulfonation NOH Co-oxidation N-nitrosobiphenyl Haemoglobin adducts nitrinium cation DNA proteins Adducts N O N H OSO 3 -
1.3.3.2 Aristolochic acid (AA) 29 Introduction Not only the environmental polluants or food derivative heterocyclic amines form DNA adducts, but also some fungal products contribute to carcinogenesis (305) such as aflatoxin B1 which is a fungal metabolite produced by Aspergillus flavus <strong>and</strong> related fungi that grow on improperly stored foods (306-309) . In addition, aristolochic acid (AA) is a natural product recorded for its carcinogenicity. Chinese herbs nephropathy (CHN) (310, 311) is a recently described subacute interstitial fibrosis which progress rapidly causing permanent kidney damage, including end-stage <strong>of</strong> kidney fail- ure <strong>and</strong> upper urothelial cancer. It is named also AA nephropathy (312, 313) characterising nephrotoxicity disease which is associated with the prolonged use <strong>of</strong> chinese herbs in the form <strong>of</strong> slimming pills (312, 314-316) . This syndrome has been traced to aristolochic acid (AA) which is a major alkaloid <strong>of</strong> isochinoline group extracted from Aristolochica species (316) <strong>and</strong> other plant species. It is consisting <strong>of</strong> a mixture <strong>of</strong> structurally related nitrophenanthrene derivatives, AAI <strong>and</strong> AAII (Fig. 14). <strong>The</strong>y form DNA adducts after metabolic activation by simple reduction <strong>of</strong> the nitro group (315, 316) . O O COOH OMe NO 2 Aristolochic acid I Aristolochic acid II C 17H 11NO 7 Mol. Wt.: 341.27 O O C 16H 9NO 6 Mol. Wt.: 311.25 COOH Figure 14: Chemical structures <strong>of</strong> aristolochic acid I (8-methoxy-6-nitro-phenanthro[3,4 - d][1,3]dioxole-5-carboxylic acid) <strong>and</strong> aristolochic acid II (6-nitro-phenanthro[3,4d][1,3]dioxole-5-carboxylic acid) Aristolochia is a large genus <strong>of</strong> plants with over 500 species belonging to the Birthwort family. At least 180 kinds <strong>of</strong> the plant family Aristolochiaceae are well-known over the world. It was <strong>of</strong> great interest by the ancient Egyptians, Greeks <strong>and</strong> Romans (317, 318) . Its nomenclature was developed from Greek words (Aristos: best) <strong>and</strong> (locheia: birth) meaning ‘correct delivery’. In the Indian folk medicine, it was given to women in labour to expel the placenta (319, NO 2
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 42 and 43: Introduction Finally, flavo- <stron
Page 44 and 45: Introduction chromatography with el
Page 46 and 47: Introduction One of</strong
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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