1 بسم الله الرحمن الرحيم. Presented By: Magd Mohamed Galal Professor Of Chest Diseases Al Azhar University Faculty Of Medicine For Girls 2012 2.

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بسم الله الرحمن الرحيم

Presented By:

Magd Mohamed GalalProfessor Of Chest Diseases

Al Azhar UniversityFaculty Of Medicine For Girls

20122

Discussing the relevance of genetic profiling of genes involved in mediating smoking behavior and addiction

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Although the risk of cigarette smoking is well documented, tobacco smoking continues to be the largest preventable cause of disease and premature death throughout the world.

It is estimated that there are currently still over 1.5 billion smokers worldwide , is expected to reach about 1.6–1.9 billion by 2025 .

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Inhalation of (cigarette) smoke has several deleterious effects on the airways, leading to and/or influencing chronic respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD).

According to World Health Organization estimates (in 2007), 300 million people have asthma and 210 million people have COPD.

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In contrast to other common smoking-related diseases, such as cardiovascular disease and cancer, chronic respiratory diseases are the only causes of death that are still increasing.

By 2015, about 30% of the smoking-related deaths will probably be caused by chronic respiratory diseases .

Mathers & Loncar ,2006 6

Smoke affects all people who are exposed to

it, but the degree and severity is modified by many susceptibility determinants.(Martin et al2009)

Half the world’s children are involuntarily exposed to smoke

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440,000 deaths in the U.S. each year

4.8 million deaths world wide each year

10 million deaths estimated by year 2030

50,000 deaths in the U.S. due to second-hand smoke exposure

8.6 million disabled from tobacco in the U.S. alone

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*

17

81

4119 14

30

440

0

50

100

150

200

250

300

350

400

450

Comparative Causes of Annual Deaths in the United States

Nu

mb

er

of

death

s (

thou

san

ds)

Source: Centers for Disease Control and Prevention

AIDS Alcohol Motor Homicide Drug Suicide Smoking Vehicle InducedAlso suffer from

mental illness and/or substance abuse

*9

0

5

10

15

30 40 50 60

Yea

rs o

f lif

e ga

ined

Age at cessation (years)

Prospective study of 34,439 male British doctors Mortality was monitored for 50 years (1951–2001)

On average, cigarette smokers die approximately 10 years younger than do

nonsmokers.

Among those who continue smoking, at least half will die

due to a tobacco-related disease.

Doll et al. (2004). BMJ 328(7455):1519–1527.

Absorption is pH dependent In acidic media Ionized poorly absorbed across membranes

In alkaline media Non ionized well absorbed across membranes

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At physiologic pH (7.3–7.5),nicotine is readily absorbed.

Inhaled nicotine is quickly absorbed from the large surface area of the alveoli into the pulmonary veins

Rapidly enters the arterial system Time to arterial peak is less than 10 seconds

Easily crosses blood-brain barrier and begins to reach nAchRs in ~20 seconds

Crosses the placenta freely

Appears in breast milk in concentrations ~x2 those found in blood

12Dani JA, et al (2009)

0

10

20

30

40

50

60

70

80

0 1 2 3 4 5 6 7 8 9 10

Minutes after light-up of cigarette

Pla

sma n

icoti

ne (

ng/m

L)

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Data from Henningfield et al., Drug Alcohol Depend 1993;33:23-29. Graph reprinted with permission, Rx for Change, The Regents of the University of

California, University of Southern California, and Western University of Health Sciences.

Arterial

Venous

Nicotine reaches the brain within 11 seconds

Nicotine in a cigarette = 8 to 10 mg

Each cigarette delivers 1.2-2.9 mg of nicotine

A typical pack-a-day smoker absorbs 20-40mg of nicotine each day

Half-life is ~ 2hours

During a typical day, nicotine accumulates over 6-8 hours (3-4 half-lives)

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Dani JA, et al (2009)

The increment is 5-30 ng/ml after each cigarette (depending on how the cigarette is smoked)

More frequent smoking reduces fluctuations in nicotine plasma concentration

The plateau (10-50 ng/ml) is usually reached in the early afternoon

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Dani JA, et al (2009)

Biphasic action- nicotinic acetylcholine receptors Agonist – low doses Antagonist – high doses

Although a stimulant, it is often used to relax

Works in CNS and PNS

One of the most toxic dependence-producing psychoactive compounds overall

Nicotine acts to stimulate dopamine release in mesolimbic dopamine pathway (reward center). 16

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Nicotine rises the stimulation of nicotinic receptors. The excessive and chronic activation of these receptors is balanced by a down-regulation in the number of active receptors.

The reduction of the number of active receptors reduces the psychotropic effect of nicotine. Due to the phenomenon of tolerance, the smoker needs to smoke more and more cigarettes to keep a constant effect.

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The first cigarette of the day is the most pleasant because the sensibility of the dopamine receptors is maximal. Then, the receptors are soon desensitized and the pleasure wears off.

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Tuberoinfundibular pathway Hypothalamus to Pituitary gland . Hormonal regulation . Maternal behavior (nurturing) . Pregnancy . Sensory processes

Mesolimbic and Mesocortical pathways

Ventral Tegmental Area to Nucleus Accumbens, Amygdala & Hippocampus, and Prefrontal Cortex . Memory . Motivation and emotional response . Reward and desire . Addiction . Can cause hallucinations and schizophrenia if not functioning properly

Nigrostriatal pathway Substantia Nigra to Striatum . Motor control . Death of neurons in this pathway can result in Parkinson's Disease

Nicotine enters brain

Stimulation of nicotine receptors

Dopamine release

Dopamine Reward PathwayDopamine Reward PathwayPrefrontal

cortex

Nucleus accumbens

Ventral tegmental

area

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Dopamine Pathways

Functionsreward (motivation)pleasure,euphoriamotor function (fine tuning)compulsionperserverationdecision making

Serotonin Pathways

Functionsmoodmemory processingsleepcognition

nucleusaccumbens

hippocampus

striatum

frontalcortex

substantianigra/VTA

raphe

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Neuronal structure

(receiving)

(sending)

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Vmat

transporter

DA DA

How some drugs of abuse cause dopamine release:• opioids narcotics (activate opioid receptors)• nicotine (activate nicotine receptors)

How some drugs of abuse cause dopamine release:• opioids narcotics (activate opioid receptors)• nicotine (activate nicotine receptors)

vesicle Neuronal terminal

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Perry et al. J Pharmacol Exp Ther 1999;289:1545–1552.

Nonsmoker Smoker

Human smokers have increased nicotine receptors in the prefrontal cortex.

High

Low

Image courtesy of George Washington University / Dr. David C. Perry

28Reprinted from Med Clin N Am 76(2), Benowitz NL, Cigarette smoking and nicotine

addiction, pp. 415–437, Copyright 1992, with permission from Elsevier.

Hed

on

ic S

cale Normal Affective Response

to Drugs/Alcohol

Altered Dysregulated Set-Pointfollowing chronic drug use(Koob, Science, 1997)

Hedonic Set Point is Altered with Chronic Drug Use

Initially use toget high…

Now use to “get normal”

“Cravings”

“Feel good”

“Feel bad”

Slide from Pating,D.

Metabolizedand excreted

in urine30

CH3N

H 10–20% excreted

unchangedin urine

Adapted and reprinted with permission. Benowitz et al. J Pharmacol Exp Ther 1994;268:296–303.

70–80% cotinine

~ 10% other

metabolites

N

The CYP2A6 enzyme is responsible for 90% of nicotine metabolism

80% of nicotine becomes cotinine, which becomes 3 hydroxy-cotinine

Several genetic variants for the CYP2A6 enzyme have been identified

31Hukkanen et al., 2005

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The amine function of nicotine may react with nitrogen monoxide or with nitrous acid in order to form a "nitrosonium" type molecule.

This compound may then be transformed by the body, which means oxidized and opened. This opening leads to two isomers, two "nitrosamino" type molecules (R2N-N=O) where one of the two R group is a methyl.

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In acidic medium, the oxygen of the "nitrosamine" group is protonated and the double bond moves to the central nitrogen, which becomes positively charged. This new molecule is a methyl source. The "nitrosamine" group can then react with another amine, which removes the positive charge from the nitrogen.

If the amine that reacts is a part of the structure of the DNA, an irreversible alkylation of the DNA occurs

This alkylation is really  noxious and may help in the development of cancer as it prevents the normal development of the cell.

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Tobacco smoking is believed to be a complex, multi factorial behavior with both genetic and environmental determinants.

More recent studies have found significant genetic influences on several aspects of smoking behavior.

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It has been demonstrated that genetic factors account for approximately

40–75% of the variation in smoking initiation, 70–80% of the variation in smoking

maintenance, about 50% of the variance in cessation

success and 30–50% of the variance in risk of

withdrawal symptoms . ( Xian 2003- Pergadia 2006) 37

Variations in several genes have been suggested to contribute to smoking behavior, and research has been focused on two broad classes of candidate genes:

Genes that may influence the response to nicotine Nicotine metabolism, Nicotinic receptors

Genes that may predispose to addictive behavior due to their effects on key neurotransmitter pathways Dopamine and Serotonin. (MacLeod 2006-Batra 2003) 38

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The major genes responsible for the metabolism of nicotine are the hepatic enzymes cytochrome P450 2A6 (CYP2A6) and cytochrome P450 2D6 (CYP2D6).

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CYP2A6 genetic variants predict level of smoking and nicotine dependence, and severity of withdrawal

41Malaiyandi et al., 2006; Kubota et al., 2006

Nicotine Dependence

Smoking Rate

Withdrawal Symptoms

3HC/cotinine ratio represents rate of metabolism (smaller value = slower metabolism)

Those with genetic variants thought to slow metabolism have a lower 3/HC/cotinine ratio

Proof of principle and verification of 3HC/cotinine as a phenotypic marker of CYP2A6 genetic variants

42Malaiyandi et al., 2006; Lerman et al., 2006

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44

45

0

5

10

15

20

25

30

*1/*1x2(N=8)

*1/*1(N=155)

*1/*4(N=12)

*4/*4(N=1)

Nic

oti

ne-d

2 C

leara

nce

(m

l/m

in/k

g)

Duplication (*1x2) clearance

Inactive alleles (*4) clearance

Hukkanen et al., 2005

Ultra metabolisers were found to be more likely to be heavy smokers

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(Benowitz et al 2002). 47

The rate of nicotine metabolism is faster in women than men (Benowitz et al 2006).

Among women, nicotine metabolism is faster in women taking estrogen-containing oral contraceptives, and is even faster during pregnancy, compared with other women.

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1Schnoll et al. (2007) Curr Psychiatry Rep, 9:349-357. 2Hutchison et al. (2007) Arch Gen Psychiatry, 64(9):1078-1086.

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Investigators have examined the association between smoking behavior and variations in several genes involved in the dopamine pathway, such as Dopamine receptors, The dopamine transporter and Enzymes involved in dopamine synthesis

and metabolism . 52(Balfour 2004)

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54( Laucht et al 2005)

(Lerman et al 1999) 55

(Zhang et al, 2006) 56

In addition to direct and indirect stimulation of neurotransmitter release, chronic cigarette smoking (but not nicotine administration) reduces brain monoamine oxidase A and B (MAO A and MAO B) activity, which would be expected to increase mono aminergic neurotransmitter levels such as dopamine and nor epinephrine in synapses, thus augmenting the effects of nicotine and contributing to addiction .

57MansvelderHD,&McGeheeDS.2002.

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Smoke affects all people who are exposed to it, but the degree and severity is modified by many susceptibility determinants

Genetic factors account for approximately,40–75% of the variation in smoking initiation, 70–80% of the variation in smoking maintenance, about 50% of the variance in cessation success and 30–50% of the variance in risk of withdrawal symptoms .

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Presented by

Prof. Magd Mohamed Galal