TOBACCOThe Major Etiologic and Risk Factor of the Development of Cancer and Nonneoplastic diseasesDepartment of PathologyGdjah Mada University School of Medicine

Absorption & Distribution of Toxicants

SMOKINGIs the largest single preventable cause of death in the USA (440,000 premature deaths per year)Direct health cost: tens of billions of dollars a year ($157 billion)Estimates have incriminated tobacco in:- 11-30% of cancer deaths - 17-30% of cardiovascular deaths- 30% of deaths from lung diseases (other than cancer)- 20-30% of the incidence of low-birth-weight infantsAdalah penyebab tunggal terbesar dicegah kematian di Amerika Serikat (440.000 kematian prematur per tahun)Biaya kesehatan langsung: puluhan miliar dolar per tahun ($ 157 miliar)Perkiraan telah dicurigai tembakau di:- 11-30% kematian akibat kanker- 17-30% kematian kardiovaskular- 30% dari kematian akibat penyakit paru-paru (selain kanker)- 20-30% dari kejadian bayi lahir rendah berat

SMOKINGThe major diseases responsible for the excess mortality in cigarette smokers are (in order of frequency):- coronary heart disease- cancer of the lung- COPD (chronic bronchitis and emphysema)Beginning in the World War I, annual cigarette consumption increased in men, followed by women reaching a peak of 4336 cigarettes per capita in 1963 declined to less than 3000 in 1995

Penyakit utama yang bertanggung jawab atas kematian kelebihan perokok adalah (dalam urutan frekuensi):- Penyakit jantung koroner- Kanker paru-paru- PPOK (bronkitis kronis dan emfisema)Dimulai pada Perang Dunia I, konsumsi rokok tahunan meningkat pada pria, diikuti oleh perempuan mencapai puncak 4336 batang rokok per kapita pada tahun 1963 menurun menjadi kurang dari 3000 pada tahun 1995

SMOKINGEarly exposure to carcinogens in tobacco smoke may increase risk of developing lung cancer among children and adolescents smoking continues to be a major public health problem

Smoking may interacts with other environmental and occupational exposures in additive or synergistic fashion (cigarette smokers exposed to asbestos increase in risk of lung cancer)Paparan awal karsinogen dalam asap tembakau dapat meningkatkan risiko terkena kanker paru-paru antara anak-anak dan remaja merokok terus menjadi masalah kesehatan masyarakat yang utama Merokok dapat berinteraksi dengan paparan lingkungan dan pekerjaan lainnya di aditif atau mode sinergis (perokok terpapar asbes meningkat risiko kanker paru-paru)

Absorption at Portals of EntryThe inhaled agents of cigarette smoke may act directly on the:Mucous membranesMay be swallowed in salivaMay be absorbed into the bloodstream from the abundant alveolar capillary bedAgen dihirup dari asap rokok dapat bertindak langsung pada:-membran mukosa-Itu ditelan dalam saliva-Dapat diserap ke dalam aliran darah dari kapiler alveolar berlimpah

The mainstream of the cigarette smokeParticulate phaseTar: is the total particulate phase without water and nicotine- 0.3 3.3 particles per milliliter of mainstream smoke - more than 4000 constituents including 43 known carcinogensCarcinogenic metals: As, Ni, Cd, CrPotential promoters: acetaldehyde, phenolIrritants: nitrogen dioxide, formaldehydeNicotineGas phaseCarbon monoxide

Arus utama dari asap rokok=fase partikulatTar: adalah total fase partikulat tanpa air dan nikotin- 0,3-3,3 partikel per mililiter asap mainstream- Lebih dari 4000 konstituen termasuk 43 dikenal karsinogenLogam Karsinogenik: As, Ni, Cd, CrPotensi promotor: asetaldehida, phenolIritasi: nitrogen dioksida, formaldehidnikotin=fase gaskarbon monoksida

Carbon monoxideColorless, odorless gas produced during incmplete combustion of fossil fuels or tobaccoIt has 200 times higher affinity for Hb than O2 does Exposure CO decreases the delivery of O2 to peripheral tissueBinds to other heme-comtaining protein such as myoglobin and cytochrome oxidaseTidak berwarna, tidak berbau gas yang dihasilkan selama pembakaran incmplete bahan bakar fosil atau tembakauIni memiliki 200 kali afinitas yang lebih tinggi untuk Hb daripada O2 tidak CO Paparan mengurangi pengiriman O2 ke jaringan periferMengikat protein heme-comtaining lain seperti mioglobin dan sitokrom oksidase

Nicotine Important constituent of cigarette smokeNicotine is responsible for tobacco addictionAlkaloid that readily crosses the blood-brain barrier stimulate nicotine receptor pharmacologic effects associated with tobacco use (most likely mediated by catecholamines):- increased heart rate & blood pressure- increased coronary artey blood flow- increased contractility and cardiac output- increased mobilization of fatty acidsKonstituen penting dari asap rokokNikotin bertanggung jawab atas kecanduan tembakauAlkaloid yang mudah melintasi penghalang darah-otak merangsang reseptor nikotin efek farmakologis yang terkait dengan penggunaan tembakau (kemungkinan besar dimediasi oleh katekolamin):- Peningkatan denyut jantung & tekanan darah- Peningkatan aliran darah koroner artey- Peningkatan kontraktilitas dan curah jantung- Peningkatan mobilisasi asam lemak

Organ Specific Carcinogens in Tobacco Smoke

Lung, larynxPolycyclic aromatic hydrocarbon4-(Methylnitrosoamino)-1-(3-pyridyl)-1-butanone (NNK)Polonium 210Esophagus N-Nitrosonornicotine (NNN)PancreasNNK (?)Bladder4-Aminobiphenyl, 2-naphthylamineOral cavity (smoking)Polycyclic aromatic hydrocarbon, NNK, NNN

Oral cavity (snuff)NNK, NNN, Polonium 210

The risk of dying in smokers and nonsmokers

Cardiovascular Disease is a Major Complication of SmokingCigarette smoking is recognized as a major independent risk factor for myocardial infarction, and acts synergistically with other risk factors such as high blood pressure and elevated blood cholesterol levelsAtherosclerosis of coronary arteries and the aorta is more severe and extensive among cigarette smokers than among nonsmokers, and the effect is dose related

Merokok diakui sebagai faktor risiko independen utama untuk infark miokard, dan bertindak secara sinergis dengan faktor-faktor risiko lain seperti tekanan darah tinggi dan kolesterol darah tinggiAterosklerosis arteri koroner dan aorta lebih parah dan luas di antara perokok dibandingkan bukan perokok kalangan, dan efeknya adalah dosis terkait

The risk of myocardial infarction in cigarette smokers

Cancer of the Lung is Largely a Disease of Cigarette SmokersMore than 85% of deaths from cancer of the lung are attributed to cigarette smoking, the single most common cancer in both men and women in the USA today

Lebih dari 85% kematian akibat kanker paru-paru yang disebabkan merokok, kanker yang paling umum tunggal dalam pria dan wanita di Amerika Serikat hari ini

Diseases associated with cigarette smoking

Death rate from lung cancer among smokers & non-smokers

Dose dependent relationship between cigarette smoking and the risk of lung cancer

Dose dependent relationship between cigarette smoking and the risk of pancreatic cancer

Xenobiotic metabolismPhase I reaction :Aromatic Hydroxilation and EpoxidationOxidation by FMO SystemPeroxidase-Dependent CooxidationReduction of NADPH-Cytochrome P-450 ReductasePhase II Reactions :Activation by GlucuronidationBiomethylationActivation by Cytochrome P-450 and Detoxification by Glutathion Conjugation

Tahap I reaksi:Aromatic Hydroxilation dan EpoksidasiOksidasi oleh Sistem FMOPeroksidase-Dependent CooxidationPengurangan NADPH-sitokrom P-450 ReduktaseTahap II Reaksi:Aktivasi oleh glucuronidationBiomethylationAktivasi oleh sitokrom P-450 dan Detoksifikasi oleh glutathione Konjugasi

Xenobiotic metabolismPhase I reaction :Aromatic Hydroxilation and Epoxidation (benzo(a)pyrene covalent binding to DNA lung & skin cancer)Oxidation by FMO (flavin-containing monooxygenase) System (Nicotine Nicotine-1-N-oxide)Peroxidase-Dependent Cooxidation (2-Naphthylamine self coupling)Reduction of NADPH-Cytochrome P-450 Reductase (Paraquat)Tahap I reaksi: 1. Aromatic Hydroxilation dan epoksidasi (benzo (a) pyrene kovalen mengikat DNA paru-paru & kanker kulit) 2. Oksidasi oleh FMO (flavin yang mengandung monooxygenase) System (Nikotin Nikotin -1'-N-oksida) 3. Peroksidase-Dependent Cooxidation (2-naftilamina coupling diri) 4. Pengurangan NADPH-sitokrom P-450 Reduktase (Paraquat)

Xenobiotic metabolismPhase II Reactions :Activation by Glucuronidation (2-Naphthylamine N-Hydroxy- 2-Naphthylamine Bladder cancer)Biomethylation (inorganic mercury dimethyl mercury)Activation by Cytochrome P-450 and Detoxification by Glutathion Conjugation(Vinyl chloride covalent binding to macromolecules cancers?)Tahap II Reaksi:Aktivasi oleh glucuronidation (2-naftilamina N-Hydroxy-2-naftilamina kandung kemih kanker)Biomethylation (merkuri anorganik dimetil merkuri)Aktivasi oleh sitokrom P-450 dan Detoksifikasi oleh glutathione Konjugasi (Vinyl chloride kovalen mengikat makromolekul kanker?)

Death per Year Attributable to Cigarette Smoking in the US

Cause of DeathNo.of Death (Men)No.of Death (Women)Cancer102,81254,664Cardiovasc.disease90,90657,699Respiratory disease53,71344,429Residential fires589377Perinatal death598407Lung cancer & heart disease attributable to passive smoking15,51722,536Total264,13580,112

Lung cancer

Lung cancer(squamous cell carcinoma)

Lung cancer(small cell carcinoma)

Smokers Develop Nonneoplastic DiseasesChronic bronchitis & emphysema are primarily dose-related disease of smokersPeptic ulcer disease has 70% greater prevalence in male cigarette smokers than nonsmokersOsteoporosis: women who smoke > I pack at the time of menopause exhibit 5-15% deficit in bone density enough to increase the risk of bone practureThyroid disease Graves diseaseOccular disease macular degeneration & cataract

Bronkitis kronis & emfisema terutama yang berhubungan dengan dosis penyakit perokokUlkus peptikum memiliki prevalensi 70% lebih besar pada perokok dibandingkan bukan perokok laki-lakiOsteoporosis: wanita yang merokok> saya pak pada saat menopause pameran 5-15% defisit kepadatan tulang cukup untuk meningkatkan risiko tulang practurePenyakit tiroid penyakit Graves Penyakit occular degenerasi makula & katarak

The association between cigarette smoking and pulmonary emphysema

EMPHYSEMA

Smoking Impairs Female Reproductive Function

Effect of smoking on birth weight

Effect of smoking on the incidence of abruptio placentae

Effect of smoking on the incidence of placenta previa

Effect of smoking on the incidence of the premature rupture of membrane

Passive Smoking is defined as Exposure of Nonsmokers to Smoke Produced by Tobacco SmokersRisk associated with exposure to sidestream smoke also called environmental tobacco smoke (ETS)Especially hazardous to infants and young children (sudden infant death syndrome, increased incidence of respiratory and ear infection, exacerbation of asthma)

Merokok pasif didefinisikan sebagai Paparan Bukan Perokok ke Smoke Diproduksi oleh Tembakau Perokok Risiko yang terkait dengan paparan asap sidestream juga disebut asap tembakau lingkungan (ETS) Terutama berbahaya bagi bayi dan anak-anak (bayi mendadak sindrom kematian, peningkatan kejadian pernapasan dan infeksi telinga, asma eksaserbasi)

Diseases Associated with Cigarette SmokingCancers incidences are known to be increased in cigarette smokersNon-neoplastic Diseases Associated with Cigarette Smoking (on the right)

RESUMECardiovascular Disease is a Major Complication of SmokingCancer of the Lung is Largely a Disease of Cigarette SmokersSmokers Develop Nonneoplastic DiseasesSmoking Impairs Female Reproductive FunctionPassive Smoking is defined as Exposure of Nonsmokers to Smoke Produced by Tobacco Smokers

Penyakit kardiovaskular merupakan komplikasi utama dari Merokok Kanker Paru adalah Sebagian besar merupakan Penyakit Perokok Rokok Perokok Mengembangkan Penyakit nonneoplastic Merokok merusak Perempuan Fungsi Reproduksi Merokok pasif didefinisikan sebagai Paparan Bukan Perokok ke Smoke Diproduksi oleh Tembakau Perokok