![Toxicology of Benzo[a]pyrene
Cigarette smoke
Olaniyi Olayinka
Saint Louis University](https://image.slidesharecdn.com/benzoapyrene-150226105624-conversion-gate01/85/Benzo-a-pyrene-1-320.jpg)
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Benzo[a]pyrene
- 1. Toxicology of Benzo[a]pyrene Cigarette smoke Olaniyi Olayinka Saint Louis University
- 2. Overview • Introduction • Constituents of Cigarette smoke • Nicotine • Tar • Toxicology of Benzopyrene
- 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
- 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
- 11. Carcinogens
- 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
- 19. B[a]P • Exposure: Inhalational (Nose, Mouth) • Exposure Sites: Lungs (size of particles, molecules), Nose-Alveoli
- 20. TOXICOKINETICS
- 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
- 23. 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 (O2 2- ), Superoxide anion (O2 ·-) and Hydroxyl radical (OH·)] http://www.ncbi.nlm.nih.gov.ezp.slu.edu/pmc/articles/PMC2423818/
- 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/
- 26. http://www.ncbi.nlm.nih.gov.ezp.slu.edu/pmc/articles/PMC2423818/ Metabolic pathways of B[a]P in humans
- 27. Excretion • Hepatobiliary excretion and elimination in faeces irrespective of route of entry • Minor quantities excreted in Urine.
- 28. TOXICODYNAMICS
- 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.