Date post: | 15-Jul-2015 |
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Health & Medicine |
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Overview
• Introduction
• Constituents of Cigarette smoke
• Nicotine
• Tar
• Toxicology of Benzopyrene
Introduction
• Cigarette is a highly sophisticated nicotine delivery system primarily made from processed leaves of the tobacco plant (Nicotiana tabacum)
• Tobacco is commonly smoked.
• Can also be chewed, sniffed.
http://www.ikisan.com/links/ap_tobaccoClimate%20And%20Soils.shtml
https://docs.google.com/viewer?url=http://www.cdc.gov/nchs/ppt/hp2010/focus_areas/fa27_charts.ppt&pli=1
Health effects
• Causal effects of smoking largely based on observational studies
• American Cancer Society- 1M, 9yrs, 80K deaths
• British Medical Research Council- 34K, 40yrs, 20K deaths.
Corbin Grady Studio/Science Photo Library
Constituents of Cigarette smoke
• Mainstream – drawn through the tobacco column, exits through the mouthpiece during puffing (0.1 to 1𝜇m)
• Sidestream – emitted from the smouldering tobacco between puffs (0.01 to 0.1𝜇m)
• Products of incomplete combustion
• Particulate phase vs. Gas Phase
Constituents of Cigarette
• Nicotine
• Carbon-monoxide
• Tar, over 4000 chemicals- WHO 18 mainstream smoke constituents, 7 “Most hazardous.” (FCTC)
Nicotine,
• Natural product of tobacco, t1/2 1-2hours
• Addiction, tolerance, dependence,
• Vd > total BW (mean 88± 17L)
• Crosses BBB easily
• Effects of Dopamine, NE, E release and metabolism
• Liver- CY P450- Cotinine, Nicotine N-Oxide
http://lib.bioinfo.pl/meid:8527
Tar
• describes the particulate matter inhaled when the smoker draws on a lighted cigarette.
• Each particle is composed of a large variety of organic and inorganic chemicals.
• Condensate form is a sticky brown substance.
• Carcinogens: Polycyclic aromatic hydrocarbons, tobacco-specific nitrosamines, metals
Poly-aromatic Hydrocarbon
• Polycyclic organic matter
• Epidemiologic studies have reported increase in lung cancer in humans exposed.
• Animal studies have reported Respiratory tract tumors from inhalation exposure to benzo[a]pyrene and stomach tumors, leukemia, and lung tumors from oral exposure to benzo[a]pyrene.
Benzo[a]pyrene (B[a]P)
• Physical Properties
• 5-ring PAH = Benzene ring fused to Pyrenemolecule with chemical formula C20H12, MW= 252.3 g/mol
• Melting point= 179 °C , BPt.= 495 °C
• Vapor pressure of 5.6 × 10-9 mm Hg at 25 °C.
• log octanol/water partition coefficient (log Kow) of 6.06, H2O solubiity= 0.11mg/L
Risk assessment
• Hazard Identification- IARC Group 1 carcinogen
• Cancer and Non-Cancer effect
• Epidemiologic studies- Humans, Animals
• Reproductive/Developmental
• Mathematical models: CalEPA- inhalation unit risk estimate of 1.1 x 10-3 (µg/m3)-1
http://www.epa.gov/ttnatw01/hlthef/polycycl.html
• EPA has not established a Reference Concentration or a Reference Dose for benzo[a]pyrene
• Low tar cigarettes- 10ng B[a[P/cigarette on average
B[a]P
• Exposure: Inhalational (Nose, Mouth)
• Exposure Sites: Lungs (size of particles, molecules), Nose-Alveoli
Absorption
• Highly lipid-soluble, Lung, Gut and Skin
• Bronchial clearance, ciliated mucosa, penetration of cells where metabolism takes place.
• 85% initial dose cleared within 30mins.
Distribution
• Distributes readily in all body tissues
• Detectable levels in mins-hours highest in Liver
• Rapid metabolism occur preventing accumulation, even in fat cells
Metabolism
• Toxicokinetics
• Absorption by Lung epithelial cells
• Cellular transformation: Bioactivation
• Peroxidase Cycle: CY P450 Peroxidase, Air, CY P450 Reductase, NADH- CY b5 Reductase
• Yield: Radical Cation, Quinones, Peroxide (O22-
), Superoxide anion (O2·-) and Hydroxyl radical
(OH·)]
http://www.ncbi.nlm.nih.gov.ezp.slu.edu/pmc/articles/PMC2423818/
• Mono-oxygenation: NADPH- dependent CY P450 isoforms (1A1 and 1B1) to yield areneoxides.
• Rearrange 3,7, or 9-OH-B[a]P or
• Hydrated by Epoxide Hydrolase to yield B[a]P dihyrodiols
• Further mono-oxygenation to anti-B[a]P-7,8-diol-9,10 epoxide (anti-B[a]PDE)- Rat carcinogen
http://www.ncbi.nlm.nih.gov.ezp.slu.edu/pmc/articles/PMC2423818/
• In Humans – B[a]P-dihydrodiols can also be oxidized by aldo-keto reductase (AKR1A1, 1c1-1C4)
• Yields Ketol→ Cathecol (Unstable)
• Undergoes autooxidation (1e-) in air → Semiquinone anion radical → Michealacceptor, B[a]P-7,8-dione and ROS
• ↓B[a]P-7,8-dione → Cathecol →vicious circle
http://www.ncbi.nlm.nih.gov.ezp.slu.edu/pmc/articles/PMC2423818/
http://www.ncbi.nlm.nih.gov.ezp.slu.edu/pmc/articles/PMC2423818/
Metabolic pathways of B[a]P in humans
Excretion
• Hepatobiliary excretion and elimination in faeces irrespective of route of entry
• Minor quantities excreted in Urine.
• Inhaled dose depends on smoking behaviour, cig. type.
• Effect mediated by metabolites of B[a]P
• Local vs. Systemic
• Lipid Peroxidation, DNA Mutation
• Initiation and Promotion.
• Reversibility? Need > single mutation.
Carcinogenesis
• B[a]P-radical-cations- depurinating adducts-covalent binding to nucleic acid base (Guanine)
• B[a]P-1,6- and B[a]P-3,6-dione- activate EGF
• anti-B[a]PDE- stable bulky DNA adducts, activates ras proto-oncogene.
• Reacts with p53 tumor suppressor gene to form adducts in specific codons – Most mutated regions in Lung Cancer Patients.
Conclusion
• Benzo[a]pyrene, a Group 1 carcinogen, is a well established constituent of mainstream/sidestream cigarette smoke
• Animal studies have confirmed the carcinogenic effects of B[a]P especially in Respiratory system
• Convincing large human epidemiological studies in USA, Britain, Japan, Germany etc.