This document summarizes the toxicology of benzopyrene, a constituent of cigarette smoke. It discusses how benzopyrene is absorbed in the lungs and distributed throughout the body, where it is metabolized through pathways that can form reactive compounds causing DNA damage and cancer. The document outlines how benzopyrene exposure from smoking can lead to local effects in the lungs as well as systemic effects like lipid peroxidation and mutations causing cancer through DNA adduct formation and activation of oncogenes.

1. TOXICOLOGY OF A
CONSTITUENT OF CIGARETTE
SMOKE
Olaniyi Olayinka

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.
 It can also be chewed, sniffed.
http://www.ikisan.com/links/ap_tobaccoClimate%20And%20Soils.shtml

4. https://docs.google.com/viewer?url=http://www.cdc.gov/nchs/ppt/hp2010/foc
us_areas/fa27_charts.ppt&pli=1

5. Health effects
 Causal effects of smoking are largely based on
observational studies
 Earliest epidemiological studies on health effects of
tobacco use were conducted by Sir Richard Doll
 According to the American Cancer Society, tobacco
use accounts for at least 30% of all cancer deaths
and 80% of lung cancer deaths

6. BMJ 1998 Uncovering the risks of smoking; A historical Perspective. Latency period of
cancer development

7. Constituents of Cigarette smoke


8. Constituents of Cigarette
 Nicotine
 Carbon-monoxide
 Tar and thousands of chemicals few of which are
discussed in later slides
 “Studies are yet to provide evidence of significant health
benefits associated with smoking lower-tar cigarettes.”

9. Nicotine,
 The natural product of tobacco,
 Has a half life of approx. 1 to 2 hours and
 Volume of distribution = (mean 88± 17Litres)
 Crosses blood-brain barrier which explains its addictive
property and nicotine dependence
 Affects release and metabolism of neurotransmitters
such as dopamine, norepinephrine, and epinephrine .
 It is metabolized by Liver enzymes to Nicotine N-Oxide
and Cotinine
 Cotinine is a popularly used biomarker of tobacco
exposure
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.
 Contains known carcinogens such as polycyclic
aromatic hydrocarbons (PAH), tobacco-specific
nitrosamines, certain metals

11. Poly-aromatic Hydrocarbon
 Polycyclic organic matter e.g. benzo[a]pyrene
 Epidemiologic studies have reported a link between
lung cancer and exposure to PAH
 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.

12. Benzo[a]pyrene (B[a]P)
 B[a]P was determined in 1933 to be the component
of coal tar responsible for the first recognized
occupation-associated cancers, the sooty
warts (cancers of the scrotum) suffered by chimney
sweeps in 18th century England.
 It is a 5-ring PAH (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

13. Risk assessment
 IARC classified B[a[P as a Group 1 carcinogen
 California EPA established an inhalation unit risk
estimate of 1.1 x 10-3 (µg/m3)-1 for B[a[P
 However, EPA is yet to establish a Reference
Concentration or a Reference Dose for
benzo[a]pyrene
 Low tar cigarettes contains approx. 10ng of B[a[P
per cigarette on average
http://www.epa.gov/ttnatw01/hlthef/polycycl.html

14. B[a]P
 Exposure: Inhalational (Nose, Mouth)
 Exposure Sites: Lungs (size of particles, molecules),
Nose-Alveoli

15. How our body handles B[a]P

16. 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.

17. Distribution
 Distributes readily in all body tissues
 Detectable levels in mins to hours highest in Liver
 Rapid metabolism occur preventing accumulation,
even in fat cells

18. Metabolism
 Absorption occurs by Lung epithelial cells
 Cellular transformation
A. Bioactivation
 Peroxidase Cycle requires: CY P450 Peroxidase, Air,
CY P450 Reductase, NADH- CY b5 Reductase
 Products: Radical Cation, Quinones, Peroxide (O22-),
Superoxide anion (O2·-) and Hydroxyl radical (OH·)]
 Products are highly reactive free radicals with a
wide range of harmful health effects
http://www.ncbi.nlm.nih.gov.ezp.slu.edu/pmc/articles/PMC2423818/

19. Metabolism
B. Mono-oxygenation
 NADPH- dependent CY P450 isoforms (1A1 and
1B1) convert B[a]P to arene oxides.
 3,7, or 9-OH-B[a]P are either rearranged or
hydrated by epoxide hydrolase to yield B[a]P
dihyrodiols
 Further mono-oxygenation occurs to anti-B[a]P-7,8-
diol-9,10 epoxide (anti-B[a]PDE)- a known Rat
carcinogen (check next slide for fate in humans)
http://www.ncbi.nlm.nih.gov.ezp.slu.edu/pmc/articles/PMC2423818/

20. Metabolism
 In Humans – B[a]P-dihydrodiols can also be
oxidized by aldo-keto reductase (AKR1A1, 1c1-
1C4) to produce Ketol→ Catechol (Unstable)
 Further autooxidation (1e-) in air forms Semiquinone
anion radical → Micheal acceptor, B[a]P-7,8-dione
and Reactive Oxide Species (ROS are harmful to
our health)
 Reduction in B[a]P-7,8-dione unfortunately triggers
a feedback loop leading to formation of more
Catechol generating more ROS in the process.
http://www.ncbi.nlm.nih.gov.ezp.slu.edu/pmc/articles/PMC2423818/

21. Metabolic pathways of B[a]P in humans
http://www.ncbi.nlm.nih.gov.ezp.slu.edu/pmc/articles/PMC2423818/

22. Excretion
 Hepatobiliary excretion and elimination in faeces
occur irrespective of route of entry
 Small quantity of B[a]P is excreted in Urine.

23. What B[a]P really does to our health!

24.  Inhaled dose depends on smoking behaviour, cig.
type.
 Effect mediated by metabolites of B[a]P
 Local as well as Systemic effects occur e.g.
 Lipid Peroxidation especially of cell membranes
(cell damage), DNA Mutation

25. Carcinogenesis
 B[a]P-radical-cations forms depurinating adducts
i.e. 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- is a 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.

26. 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
have been conducted in USA, Britain, Japan,
Germany to name a few etc.
 Consider the harmful health effects of cigarette
smoking!!!