3. 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
5. 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
6.
7. 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
8. Constituents of Cigarette
• Nicotine
• Carbon-monoxide
• Tar, over 4000 chemicals- WHO 18 mainstream
smoke constituents, 7 “Most hazardous.”
(FCTC)
9. 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
10. 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
14. 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.
15. Benzo[a]pyrene (B[a]P)
• Physical Properties
• 5-ring PAH = Benzene ring fused to Pyrene
molecule with chemical formula C20H12, MW=
252.3 g/mol
16. • 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
17. 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
18. • 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
21. 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.
22. Distribution
• Distributes readily in all body tissues
• Detectable levels in mins-hours highest in
Liver
• Rapid metabolism occur preventing
accumulation, even in fat cells
24. • Mono-oxygenation: NADPH- dependent CY
P450 isoforms (1A1 and 1B1) to yield arene
oxides.
• 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/
25. • 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 → Micheal
acceptor, 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/
29. • 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.
30. 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.
31. 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.