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بسم هللا الرحمن الرحيم 1 Presented By: Magd Mohamed Galal Professor Of Chest Diseases Al Azhar University Faculty Of Medicine For Girls 2012 2 Discussing the relevance of genetic profiling of genes involved in mediating smoking behavior and addiction 3 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 . 4 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. 5 In contrast to other common smokingrelated 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 7 440,000 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 8 Comparative Causes of Annual Deaths in the United States 440 450 400 350 300 250 * 200 150 81 100 50 17 41 19 14 Homicide Drug Induced 30 0 AIDS Alcohol Motor Vehicle Source: Centers for Disease Control and Prevention Suicide Smoking suffer from mental *Also illness and/or substance abuse 9 Prospective study of 34,439 male British doctors Mortality was monitored for 50 years (1951–2001) Years of life gained 15 On average, cigarette smokers die approximately 10 years younger than do nonsmokers. 10 5 0 30 40 50 60 Among those who continue smoking, at least half will die due to a tobacco-related disease. Age at cessation (years) 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 At physiologic pH (7.3–7.5), nicotine is readily absorbed. 11 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 Dani JA, et al (2009) 12 Nicotine reaches the brain within 11 seconds Plasma nicotine (ng/mL) 80 70 Arterial 60 50 40 30 Venous 20 10 0 0 1 2 3 4 5 6 7 8 9 10 Minutes after light-up of cigarette 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, 13 University of Southern California, and Western University of Health Sciences. 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) Dani JA, et al (2009) 14 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 Dani JA, et al (2009) 15 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 17 18 19 Nicotine rises the stimulation of nicotinic receptors. The excessive and chronic activation of these receptors is balanced by a downregulation 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. 20 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. 21 Nigrostriatal pathway Substantia Nigra to Striatum . Motor control . Death of neurons in this pathway can result in Parkinson's Disease 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 Tuberoinfundibular pathway Hypothalamus to Pituitary gland . Hormonal regulation . Maternal behavior (nurturing) . Pregnancy . Sensory processes 22 Dopamine Reward Pathway Prefrontal cortex Dopamine release Stimulation of nicotine receptors Nucleus accumbens Ventral tegmental area Nicotine enters brain 23 Dopamine Pathways striatum frontal cortex hippocampus substantia nigra/VTA nucleus accumbens Functions reward (motivation) pleasure,euphoria motor function (fine tuning) compulsion Serotonin Pathways raphe Functions mood memory processing sleep 24 Neuronal structure (receiving) (sending) 25 stimulation Vmat vesicle Neuronal terminal transporter How some drugs of abuse cause dopamine release • opioids narcotics (activate opioid receptors) • nicotine (activate nicotine receptors) DA 26 Human smokers have increased nicotine receptors in the prefrontal cortex. High Low Nonsmoker Smoker Image courtesy of George Washington University / Dr. David C. Perry 27 Reprinted from Med Clin N Am 76(2), Benowitz NL, Cigarette smoking and nicotine addiction, 28 pp. 415–437, Copyright 1992, with permission from Elsevier. Hedonic Set Point is Altered with Chronic Drug Use “Feel good” Normal Affective Response to Drugs/Alcohol Initially use to get high… “Cravings” “Feel bad” (Koob, Science, 1997) Now use to “get normal” Altered Dysregulated Set-Point following chronic drug use Slide from Pating,D. H N N 70–80% cotinine CH3 10–20% excreted unchanged in urine ~ 10% other metabolites Metabolized and excreted in urine 30 Adapted and reprinted with permission. Benowitz et al. J Pharmacol Exp Ther 1994;268:296–303. 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 Hukkanen et al., 2005 31 32 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. 33 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. 34 35 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. 36 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 Individuals with a may experience fewer adverse reactions to their first encounter with nicotine and, therefore, may have a greater chance of continuing smoking and becoming addicted. Conversely, may be less prone to initiate smoking because they may experience more adverse effects and would require fewer cigarettes to maintain nicotine titres at an optimal level once smoking is initiated . 39 The major genes responsible for the metabolism of nicotine are the hepatic enzymes cytochrome P450 2A6 (CYP2A6) and cytochrome P450 2D6 (CYP2D6). 40 CYP2A6 genetic variants predict level of smoking and nicotine dependence, and severity of withdrawal Smoking Rate Nicotine Dependence Malaiyandi et al., 2006; Kubota et al., 2006 Withdrawal Symptoms 41 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 Malaiyandi et al., 2006; Lerman et al., 2006 42 Polymorphisms in do not seem to be major determinants of nicotine metabolism in smokers except in ultra metabolisers (gene duplication) .( Saarikoski et al 2000) This is probably because its catalytic activity towards nicotine is negligible in the presence of functional CYP2A6. 43 Smokers with dependent: level of dependence or non- Smoke small number of cigarettes per day First cigarette delayed Frequent periods off smoking – cold turkey each time Minimal withdrawal symptoms Majority of regular smokers have moderate-tosevere dependence and find it difficult to stop or cut down 44 Nicotine-d2 Clearance (ml/min/kg) 30 Duplication (*1x2) clearance 25 20 Inactive alleles (*4) clearance 15 10 5 0 *1/*1x2 (N=8) *1/*1 (N=155) *1/*4 (N=12) *4/*4 (N=1) 45 Hukkanen et al., 2005 Ultra metabolisers were found to be more likely to be heavy smokers 46 Asians and African Americans metabolize nicotine on average more than do Caucasians or Hispanics (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. 48 The pharmacological effects of nicotine are mediated by the activation of nicotinic acetylcholine receptors (nAChRs). mainly contain the α4 (CHRNA4) and β2 (CHRNB2) subunits, and α4β2* (* indicates that another subunit may be included) is the most frequently encountered nicotinic receptor subtype. Several nAChR subunit genes have been examined for associations with smoking status (e.g. CHRNA4, CHRNA5, CHRNA7, CHRNB1, CHRNB2 and CHRNB3), 49 People with polymorphism (gene coding for α4 subunit of the nicotinic Ach receptor) have higher rates of tobacco dependence. 1Schnoll et al. (2007) Curr Psychiatry Rep, 9:349-357. et al. (2007) Arch Gen Psychiatry, 64(9):1078-1086. 2Hutchison 50 51 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 . (Balfour 2004) 52 53 Variants in several (e.g. DRD1, DRD2, DRD4 and DRD5) have been detected and studied in relation to smoking behavior. Overall, genotypes associated with reduced dopamine receptor expression or function seem to predict a higher chance of becoming a smoker, a younger age of onset, and fewer and less successful quit attempts . ( Laucht et al 2005) 54 The moves the dopamine released in the synapse into a neuron, glial cell or astrocyte to terminate the dopamine signal. A reduction in resulting in levels, less clearance and greater bio-availability of dopamine, has been shown to be related to a lower chance of becoming a smoker, a lower nicotine intake and longer periods of smoking cessation (Lerman et al 1999) 55 Several , such as tyrosine hydroxylase (TH), 3,4dihydroxyphenylacetic acid decarboxylase (DDC), dopamine β-hydroxylase (DBH), catechol-O-methyl-transferase (COMT) and monoamine oxidase (MAO)-A and -B, are involved in the synthesis and metabolism of dopamine. Only limited data on the effects of variations in these enzymes on smoking behaviour are available. Associations between smoking and variations in genes for MAO-A, MAO-B, DBH and DDC have been found . (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 . MansvelderHD,&McGeheeDS.2002. 57 58 The serotonin pathway is also under investigation in genetic studies of smoking, for several reasons. , nicotine has been shown to increase the secretion of serotonin in the brain . (Mihailescu et al 1998) , increased serotonin levels have been associated with decreased food intake and weight gain, and have been shown to have an antidepressant effect . (Ribeiro et al 1993) 59 , lower serotonin re-uptake has been associated with several behavioural traits (e.g. neuroticism, novelty seeking and anxiety-related personality traits) that are related to an increased incidence of smoking, increased nicotine dependence and difficulty in quitting smoking . (Hu et al 2000) 60 Candidate polymorphisms include those involved in (TPH)) HTT)). (e.g. tryptophan hydroxylase (e.g. serotonin transporter (5- Individuals homozygous for a variant of TPH, with an unknown effect, have been shown to be more prone to initiate smoking and to start smoking at an earlier age, but no effect on progression to nicotine dependence and smoking status has been found . (Mizunoet al 2006) 61 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 . 62 Presented by Prof. Magd Mohamed Galal