A constituent of cigarette smoke

TOXICOLOGY OF A CONSTITUENT OF CIGARETTE SMOKE

Olaniyi Olayinka

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. It 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 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

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

Constituents of Cigarette smoke

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.”

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

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

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]pyreneand stomach tumors, leukemia, and lung tumors from oral exposure to benzo[a]pyrene.

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

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

B[a]P

Exposure: Inhalational (Nose, Mouth) Exposure Sites: Lungs (size of particles, molecules),

Nose-Alveoli

How our body handles B[a]P

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 to hours highest in Liver

Rapid metabolism occur preventing accumulation, even in fat cells

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/

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 orhydrated 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)


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 Semiquinoneanion radical → Micheal acceptor, B[a]P-7,8-dioneand 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.



Metabolic pathways of B[a]P in humans

Excretion

Hepatobiliary excretion and elimination in faecesoccur irrespective of route of entry

Small quantity of B[a]P is excreted in Urine.

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

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

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.

Conclusion

Benzo[a]pyrene, a Group 1 carcinogen, is a well established constituent of mainstream/sidestreamcigarette 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!!!

Health & Medicine

A constituent of cigarette smoke