Types of Lung Cancer
5.2.3 Genetic Factors That Increase the Risk for Bronchial Carcinoma
Shiftsareplainlyoccurringinthepresentationofdifferentlungcancertypes.Whilethere hasbeenaproportionaldecreaseinSCC,AChasbecomemorecommon,possiblydueto thereductioninpolynucleararomatichydrocarbonsPAHininhaledsmokefromiltered low-yieldcigarettes [27] .TheenzymesCYP1A1andGSTM1playamajorroleinthe metabolicactivationanddetoxiicationofPAH,whileCYP2E1isresponsiblemoreforthe metabolicactivationofnitrosamines.Onecase-controlstudyconductedin341incident lungcancercasescomparedwith456healthycontrolsconirmeda2.4-foldincreaseinthe riskforSCCwheretheCYP1A1MspIvariantallelewaspresent,anda3.1-foldincrease whenthiswascombinedwithaGSTM1deletion [63] .Incontrast,CYP2E1RsaIandDraI polymorphismsdidnotcorrelatewithSCCrisk;however,thepresenceoftheseenzyme variants was associated with a tenfold reduction in the risk for small cell lung cancer SCLC,whileACdevelopmentwasencouragedbyCYP2E1mutants [63] . On stratiied analysis, it is found that the polymorphic metabolicoxidative enzyme myeloperoxidaseMPOgenotypesmodiiedtheeffectofasbestosexposureonlungcancer risk.Speciically,GGcarrierswhowereexposedtoasbestoshadahigherrisk,whileA-allele carriersGA+AAshowedareducedORof0.8995CI;0.56–1.44.TheA-allelegeno- types,therefore,demonstratedprotectiveeffectsonthedevelopmentoflungcancer.5.2.3.1 Tobacco-Specific Carcinogens
Severalproductshavebeenimplicatedinthedevelopmentofcancerinsmokers:PAH, tobacco-speciic nitrosamines TSNA und aromatic amines AA. The metabolism of thesetoxicsubstancesplaysacrucialrole,andthisprocessmaybeinluencedtoamajor extentbygeneticdifferencesinthemetabolisingcytochromeP450CYPenzymesandby theglutathioneS-transferaseGSTsystem. Benzo[a]pyreneactivatesoncogenesandinteractswithDNA;italsopromotesthefor- mationofdiol-epoxidesaskeyreactivesubstances.Benzo[a]pyreneundergoestransfor- mationtophenolmetabolitesandbenzo[a]pyrene-7,8-diolebytheactionofcytochrome enzymessuchasepoxidehydrolasesandotherisoenzymes;thelatterformthehighlyreac- tive+-anti-benzo[a]pyrenediol-epoxideBPDE,whichisagoodsubstrateforGSTM1, M2,M3andanevenbettersubstrateforGSTPI [39] .Thesemetabolicproductshavealso beendetectedinlungtissueandinlymphocytes [36] . 4-Methylnitrosoamino-1,3-pyridyl-1-butanoneNNKandN′-nitrosonornicotineNNN cf.Box3.1in Chap.3 arethemostimportantTSNA;theyareformedinunburnedtobacco andduringcombustion.Smokersareprincipallyconfrontedwithbothsubstances,though NNKinparticularproducescancerintheupperrespiratorytract.Themetabolicpathways ofNNKinhumansandanimalsareidentical.NNKdosesabsorbedbyhumansaredei- nitelycarcinogenicinanimalexperiments.PriortobindingtoDNA,bothnitrosamines require activation a-methyl or a-methylene hydroxylation, pyridine-N-oxidation by CYP-mediatedreactionsandglucuronidation [64,65] .ThealcoholfromNNKisexcreted intheurineandservesasanindicatorforNNKexposure. TheAA,including4-aminobiphenyl,arecompoundsthatplayaparticularroleinthe developmentofcarcinomaofthebladder [66] andtherefore,willnotbediscussedfurther inthepresentcontext. DNAdamageisalsoproducedasaresultofoxidationprocessesandbylipidperoxida- tion.Inhaledmaterialfromtobaccocontainsoxygenandnitrogengroups,whichreactwith thevariousbodytissuesinsmokers.Consequently,oxidativeDNAdamageduetoprod- uctsformedbylipidperoxidationmalondialdehyde,crotonaldehyde,trans-4-OH-2-nonenal iscommonlyfoundintherespiratorytracttissuesofsmokers.Thesemetabolitesareepoxi- disedbyCYP-mediatedreactionsandformpromutagenicDNAadductsinhumantissue [40, 67, 68] , leading to an increased cancer risk for the upper respiratory tract [41] . Chewingtobaccowithorwithoutbetelproducescancersintheoralcavity [69] .5.2.3.2 The Cytochrome P450 and GST System and Carcinogenesis
Currentepidemiologicalresearchintocarcinogenesisinthelungindicatesthatseveralpop- ulationsareatriskforthedevelopmentoflungcancer,especiallysmokersandworkers exposedtotoxicsubstances.Onegeneticfactorthatdeservesparticularmentioninthis contextistheinductionofarylhydrocarbonhydroxylaseCYP1A1;AHH.Thisenzyme transformsthePAHproducedbycigarettesmokeintocompoundsthatarehighlycarcino- genic [70] .Inaddition,oxidationprocessesarecatalysedbytheCYP450systemandusing debrisoquine-4-hydroxylation CYP2D6 as a model reaction, a clear distinction can be drawnbetweenlungcancerpatientsandmatchedcontrols [71–73] .Wherethereisextensive hydroxylationofthe“modelsubstance”debrisoquine,theriskforthedevelopmentoflung cancerissimultaneouslyincreased.Todate,however,therearenoroutinetestsforthepro- phylacticidentiicationofsuchriskfactors.AsshownbythedatasummarisedinFig. 5.4 , therenalexcretionofcarcinogensishigherinsmokersthaninnon-smokers,withslightdif- ferencesdetectedintermsofresidentialenvironmentsuburbanorrural [56] .Severalstud- ieshavebeenconductedinpatientsaffectedbytheseproblems [66] andthekeyindingis thatmetabolitesoftheseinhaledtobaccoproductsformadductswithDNAFig. 5.4 . TheCYPsystemplaysacentralroleinthemetabolismoractivationofcarcinogens [68, 74–77] .Case-controlstudieshaverevealedassociationsbetweentobaccosmokeandcan- cerrisksforthelungs,larynx,mouth,oesophagus,kidneys,urinarysystemandbreasts. CYP1A1:PAHandAAareactivatedbytheenzyme.Approximately10ofCaucasians haveahighlyinducibleformofCYP1A1alsoknownasB[a]P-hydroxylase,inconjunc- tionwithanincreasedriskfortumoursofthebronchi,larynxandoralcavity [78] .Four differentformsofthecytochromeenzyme1A1havebeendescribedtodateTable 5.2 , thoughregrettablyseveralnomenclaturesareinuse.TheinducibilityofCYP1A1corre- lateswiththeoccurrenceofbronchialcarcinoma [80] ,withthem2mutantIle-→−ValParts
» Tobacco Plants and Their Origin Use of Tobacco for Religious Purposes
» The Appropriation of Tobacco by Europeans
» Development of the Cigarette
» Objections to Smoking on Health Grounds
» Women Won Over by the Cigarette
» The Medical Use of Tobacco in the Nineteenth Century
» Tobacco Research in the Twentieth Century
» Tobacco Consumption in the Twentieth Century
» Cigarette Smoking in the USA Since 1965
» Cigarette-Related Mortality in Different Countries
» Smokers and Other Risk Factors
» Smoking Behaviour and Educational Level in the EU
» Non-Disclosure of Findings by the Tobacco Industry
» The Cigarette as a Vehicle for Nicotine Release
» Modifications of Nicotine Release
» Maintaining Nicotine Dependence Nicotine and Dependence
» Marketing of Cigarettes with a “Reduced” Health Risk
» Compensatory Behaviour by Smokers
» Optimising Nicotine Release Nicotine and Dependence
» Importance of Absorption Rate
» Ammonium and pH Manipulation
» Cigarettes with Reduced Tar Yield
» Agonists and Antagonists of the nAChR and its Subtypes
» Effects of Nicotine on Receptors in Different Organs
» Metabolic and Hormonal Effects of Nicotine
» Central Nervous System Effects of Nicotine
» Types of Dependence Nicotine Dependence
» Molecular Biological Aspects of Dependence
» Genetic Aspects Nicotine Dependence
» Withdrawal Symptoms Nicotine Dependence
» Immunological Reactions Caused by Cigarette Smoking
» Association Between Smoking and Lung Cancer
» Tobacco-Specific Carcinogens Genetic Factors That Increase the Risk for Bronchial Carcinoma
» The Cytochrome P450 and GST System and Carcinogenesis
» Peptide Receptors, Genetic Factors That Increase the Risk for Bronchial Carcinoma
» Exogenous Factors and Lung Cancer
» Pathophysiology of COPD Cigarette Smoking and COPD
» Genetic Factors Important Risk Factors for COPD
» Occupational and Environmental Factors
» Caveats Concerning the Informative Value of Studies
» Cigarette Smoking and Bronchial Asthma in Adults
» Bronchial Asthma in Children
» Other Lung Diseases Influenced by Cigarette Smoking
» Coronary Artery Disease and Myocardial Infarction
» Changes in Endothelial Function and Microcirculation
» Microcirculation and O Systemic Vascular Changes
» Arteriosclerotic and Inflammatory Vascular Reactions
» Genetic Factors Blood Coagulation and Fibrinolysis
» Nicotine and Ischaemic Heart Disease
» Cognitive Impairment Central Nervous System
» Influence on Cognitive Performance
» Intellectual Impairment in Childhood
» Smoker Personality Profiles and Genetic Inheritance of Smoking
» Peculiarities of the Smoker’s Personality
» Reasons for Increased Cigarette Consumption
» Comorbidity Between Depression and Smoking
» Extent of Cigarette Consumption
» Effects of Smoking in Forms of Dementia
» Smoking and Parkinson’s Disease
» Diabetic Retinopathy Ocular Diseases
» Graves’ Ophthalmopathy Ocular Diseases
» Macular Degeneration Ocular Diseases
» Ocular Tumours Ocular Diseases
» Retinal Detachment Ocular Diseases
» Lipid and Cholesterol Metabolism
» Insulin Resistance Diabetic Nephropathy
» Oesophageal Cancer Gastrointestinal Tract
» Gastrointestinal Ulcers Gastrointestinal Tract
» Cancers of the Gastrointestinal Tract
» Pancreatic Cancer Gastrointestinal Tract
» Toxic Substances and Inducers
» Kidney Cancer Urinary Tract Diseases
» Bladder Cancer Urinary Tract Diseases
» Prostatic Hyperplasia and Prostatic Cancer
» Fertility Disorders Urinary Tract Diseases
» Vitamin D and Oestrogen Metabolism
» Osteoporosis Disorders of Mineral Metabolism and Bone
» Hip Fractures Disorders of Mineral Metabolism and Bone
» Skin Changes Skin and Mucosa
» Skin Tumours Skin and Mucosa
» Breast Cancer Skin and Mucosa
» Effects of Smoking on the Placenta
» Malformations Possibly Caused by Smoking
» Smoking and Sudden Infant Death Syndrome SIDS
» Effects of Nicotine on the Foetus
» Medical Care Costs Attributable to Smoking During Pregnancy
» ETS in the Workplace and at Home
» Fibrinogen Cholesterol Endothelium and Platelets
» Markers of Inflammation Changes at the Molecular and Cellular Level
» Passive Smoking During and After Pregnancy
» Coronary Heart Disease Cardiovascular Disease
» Stroke and Subarachnoid Haemorrhage
» Respiratory Tract in Children and Teenagers
» Bronchial Carcinoma Respiratory Tract
» Indications and Diagnostic Considerations
» Self-Help Interventions by the Smoker
» Physician Advice for Smoking Cessation
» Group Behaviour Therapy Programmes
» Mass Media Communication Strategies
» E-Learning, Email and Internet for Smoking Cessation
» Evaluation of Nicotine Products
» Nicotine Chewing Gum Nicotine
» Nicotine Sublingual Tablet Nicotine Nasal Spray
» Treatment and Dosage Nicotine
» Nicotine Chewing Gum Adverse Events Associated with NRT
» Nicotine Patch Adverse Events Associated with NRT
» Nicotine Nasal Spray Adverse Events Associated with NRT
» Nicotine Inhaler Adverse Events Associated with NRT
» Nicotine Sublingual Tablet Adverse Events Associated with NRT
» Nicotine Lozenge Adverse Events Associated with NRT
» Drug Interactions During Smoking Cessation
» Contraindications for the Use of Nicotine Products
» Nicotine Formulations as OTC Products
» Contraindications and Drug Interactions
» Tranquillisers and Buspirone Other Pharmacotherapies
» Various Antidepressants Other Pharmacotherapies
» Opioid Antagonists Other Pharmacotherapies
» Silver Acetate Other Pharmacotherapies
» Therapeutic Monitoring in Smoking Cessation
» Ischaemic Heart Disease Special Therapeutic Situations
» Pregnancy Special Therapeutic Situations
» Weight Gain Special Therapeutic Situations
» Alcohol Consumption Special Therapeutic Situations
» Organic Depression Organic Depression and Schizophrenia
» Schizophrenic Patients Organic Depression and Schizophrenia
» Interactions Between Cigarette Smoking and Administration of Psychopharmaceuticals
» Pre-operative Smoking Cessation Special Therapeutic Situations
» Social Influence Inoculation Strategy
» Life Skills Strategy Prevention Programmes for Schools
» Class 2000 Health Promotion Programme
» Trier University Health Programme Long-Term Studies
» Role of Teachers in Primary Prevention
» Prevention by Restricting Sales of Tobacco Products to Minors
» Role of the Mass Media in Sales of Tobacco Products to Adolescents
» Role of Government and Community in Primary Prevention
» Effect of Tobacco Industry Advertising Messages
» Tobacco Advertising and Adolescent Smoking Initiation
» Advertising with “Light” Cigarettes
» Smoking Bans in Public Buildings and Public Spaces
» Tobacco Industry, Governmental and Non-governmental Organisations
» Politicians and Their Attitude to Smoking
» Scientists and the Tobacco Industry
» Governmental Control of Toxic Tobacco Constituents
» Bans on Advertising in Various Countries
» Tobacco Industry: Playing Down the Risks of Smoking and Passive Smoking
» Smoking and Non-smoking: Weighing the Benefits
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