Tobacco



Smoke bomb

 

Biju C Mathew*PhD, Reji Susan Daniel PhD, Jamal Al Bahlool Bordom MD, K.T. Augusti PhD and Ian W Campbell MD look at the damning statistics of tobacco use and the deadly effects and addictive nature of tobacco.


Abstract

Smoking of tobacco products continues to be a major cause of worldwide health problems. The impact of tobacco use in terms of morbidity and mortality costs to society is staggering. The prevalence of smoking in some developed countries and the developing countries remains high or is getting higher. Smoking is one of the major risk factor of many of the world's top killer diseases-including cardiovascular disease (CVD), COPD and lung cancer, and hence is often the hidden cause of the disease recorded as responsible for death. The possible biological mechanisms responsible for the observed association of smoking with various diseases include: mutations in oncogenes and tumour suppressor genes such as KRAS and TP53, altered expression of cell cycle genes, particularly those involved in the mitotic spindle formation (e.g. TTK, NEK2, and PRC1), alterations in expression of genes associated with COPD induction and progression, increased oxidative stress, vascular endothelial dysfunction, systemic haemostatic and coagulation disturbances, lipid abnormalities, and anti-angiogenic and teratological activities. The development of nicotine dependence is thought to be linked to stimulation of the dopamine reward pathway in the midbrain. Further in-depth studies are needed to elucidate the precise mechanisms involved in the systemic effects of smoking and also nicotine addiction.

Introduction


Cigarette smoking is a serious health problem worldwide. It is the most common form of tobacco consumption and is frequently described as the leading preventive cause of mortality and morbidity throughout the world. In many developed countries the number of smokers has steadily declined over the past 20 years. However, the alarmingly high number of smokers in some developed countries and the developing countries either remains high or is getting higher. The destructive effects of smoking harm virtually every organ-system in the body, causing many diseases and compromising smoker's health in general. It would be prudent to say that smoking smokes out life. To compound matters nicotine addiction is one of most difficult addictions to overcome. In the present article we aim to review the available data on tobacco use in different countries, with emphasis on Middle East, the toxic contents in cigarette smoke, its biological effects, and nicotine addiction.

Damning statistics

The WHO Report on Global Tobacco Epidemic, 2008 presents the first comprehensive worldwide analysis of tobacco use and the impact of implementations to stop it. Currently, an estimated 1.2 billion people worldwide are smokers, and according to WHO this figure is likely to rise steeply and reach 1.6 billion by the year 2030 (1). An estimated 5 million deaths annually can be attributed to tobacco use, and if the current trend continues, it will because 10 million deaths each year by 2030, with 70% of the deaths occurring in low and middleincome countries.

Cigarette smoking is unfortunately a very common habit all over the Middle East. The Kingdom of Saudi Arabia (KSA) is the largest tobacco importer in the world. To aggravate things further, in the Middle East countries nontraditional forms of tobacco use such as water pipe smoking (WPS) (also known as hookah, shisha, narghile, goza, boory and hubble bubble) are being promoted as more safe forms of smoking and more people including youths are experimenting and using WPS regularly(2).

Table 1 provides adjusted and age-standardised data on the prevalence of tobacco use among males and females (over the age of 15) in countries of the Middle East (South West Asia), adapted from the WHO Report on Global Tobacco Epidemic, 2008(1). Jordan has the dubious distinction of having the highest prevalence of smoking among males (61.7%) and Turkey among females (20.5%). Unfortunately smoking in the medical profession in some developed countries and newly–developing countries is high, and its ramifications are detrimental to the community(3).

The deadly “aerosol cocktail mix” in cigarette smoke

Cigarette smoke (CS) is an aerosol that contains submicron liquid droplets containing a wide variety of condensed organic compounds (the particulate phase or tar phase) suspended within a mixture of gases and semi-volatile compounds (gas phase). Two kinds of smoke with different composition and properties are produced during smoking: mainstream smoke inhaled by the smoker and side stream smoke, which is released into the environment from between puffs from the lit end of the cigarette(4). Ninety percent of CS is air, water and carbon dioxide, a natural by-product of combustion. Of the remaining 10%, only a few substances such as nicotine, polycyclic aromatic hydrocarbons (PAHs) and carbon monoxide (CO) are detectable at levels above one milligram per cigarette.(5) The particulate matter of mainstream tobacco smoke (PMMTS) is viscous and approximately 80% w/w ‘tar’ where ‘tar’= total PMMTS - (nicotine+ water)(6). Thus ‘tar’ describes the nicotinefree, dry, particulate mass of tobacco smoke. In its condensable form, tar is the viscous brown substance which can stain smokers fingers and teeth yellow brown. It also stains the lung tissue. The yields of tar and nicotine in mainstream smoke of a cigarette brand as printed on the pack are measured with smoking machines under highly standardised conditions. Both the particulate and gas-phase contain very high levels of free radicals. The reactive oxygen species (ROS) are absent in unburned tobacco leaves or in cigarette ash. ROS in CS are created through combustion and exist in the gas phase or are attached to suspended particles in the particulate phase(7).

Modern analytical techniques such as nuclear magnetic resonance spectroscopy (NMR) have provided valuable information regarding the “deadly cocktail” of low-level toxins present in cigarette smoke. Over 4,000 different toxic substances, many of which are pharmacologically active, toxic, mutagenic and carcinogenic have been identified. Research has shown that at least 50 of the 4,000 different chemicals are carcinogenic. In addition another 600 additives are used in the technological process(5, 6). The major components of tobacco smoke that have been identified most likely to cause disease include: tar, nicotine, carbon monoxide, nitrogen oxides, hydrogen cyanide, aromatic amines, tobacco specific nitrosamines, polycyclic aromatic hydrocarbons, metals (nickel, arsenic, cadmium, chromium and lead), and radioactive compounds (polonium- 210, radium-226, radium-228, thorium-228 and potassium-40).(6, 8)

Table 2 lists the major known human carcinogens(6, 9). Although nicotine does not appear to possess direct carcinogenic activity itself, it enables the formation of tobacco-specific nitrosamines, which are potent carcinogens.( 10) The popular perception of WPS less harmful than cigarettes is total “farce”. Studies that have examined narghile smokers and the mainstream smoke have reported high concentrations of carbon monoxide, nicotine, “tar” and heavy metals.

These concentrations were as high as or higher than those among cigarette smokers.(11) The problem gets amplified several fold with narghile smoking held in crowded bars and cafes with improper ventilation.

How smoking kills

Non-communicable diseases (NCDs) account for the majority of the global burden of disease and, in low and middle-income countries (LMICs), are projected to increase markedly. The destructive effects of smoking harm virtually every organsystem in the body, resulting in the so-called tobacco-related diseases. Cigarette smoking accounts for at least 30% of all cancer deaths including about 87% of lung cancer deaths. Smoking has been linked to other health problems, too, including chronic obstructive pulmonary disease (COPD), respiratory tract infections, coronary artery disease (CAD), occlusive cerebrovascular disease, aortic aneurysms, peripheral vascular disease, osteoporosis, senile cataracts, peptic ulcer, infertility and sexual dysfunction.(12-14)

Smoking is one of the major risk factors of many of the world’s top killer diseasesincluding cardiovascular disease (CVD), COPD and lung cancer, and hence is often the hidden cause of the disease recorded as responsible for death. The WHO suggests that tobacco use is responsible for the death of one in ten adults worldwide. Involuntary inhalation of smoke from tobacco products (passive smoking) also can cause disease, disability and death in both adults and children.(16)

Tobacco smoke has strong biological and toxicological effects in vitro and vivo. As discussed above CS contains several known human carcinogens and substances that are probably carcinogenic to humans whose biological actions have not yet been fully established. Polycyclic aromatic hydrocarbons (benzo[a]pyrene), tobaccospecific nitrosamines, benzene, isoprene, and acetaldehyde are carcinogens present in high levels in CS.

The chemical carcinogens or tumour initiators present in CS include both the direct and indirect acting agents (chemicals that require metabolic conversion to an ultimate carcinogen). The carcinogens are mutagenic and contain highly reactive electrophilic groups that form chemical adducts with DNA, as well as with RNA and proteins. Although any gene may be the target of these chemical carcinogens, the commonly mutated oncogenes and tumour suppressor genes, such as KRAS and TP53, are important targets of chemical carcinogens. Genetic mutations seem to be more common in patients with tobacco-associated lung cancer and also other smoking- associated cancers(17, 18). Several studies have shown that mutations of KRAS and TP53 including G:C-to-T:A transversions and A:T-to-G:C transitions, are frequent in smokers with lung adenocarcinomas when compared to non smokers.(18-20) Recently, scientists have used microarray techniques to investigate the effects of smoking on gene expression profiles, in early stage lung tumours and non-tumour lung tissue of smokers, former smokers, and people who never smoked cigarettes. The researchers identified a gene expression signature characteristic of smoking that include significantly increased expression of cell cycle genes, particularly those involved in the mitotic spindle formation (e.g. TTK, NEK2, and PRC1). Changes in mitotic process are very relevant in the development of cancer. In tumour tissue of current smokers and former smokers it was noted the expression of several genes such as STOM, SSX21P, and APLP2, remained altered in participants who had quit smoking more than 20 years before the study. Hence, the changes induced by smoking at the genetic level remain unaltered even after several years among those who quit it, which can contribute to lung cancer development long after cessation. Altered expression of the cell cycle-related genes NEK2 and TTK in nontumour tissues was associated with three-fold increased risk of lung cancer mortality in smokers(21).

Cigarette-smoking – induced chronic inflammation in the lungs has been suggested as central to the pathogenesis of COPD, a common and disabling lung disease for which there are few therapeutic options. The molecular mechanisms involved in pathogenesis of COPD are poorly understood.

However, recent studies have shown that in the lungs cigarette smoking induces significant alterations in expression of genes associated with COPD induction and progression. These include genes involved in the regulation of inflammation (oxidantantioxidant imbalance and protease-antiprotease imbalance), extracellular matrix synthesis / degradation and apoptosis (tissue remodelling and repair), cytokines, chemokines and stress responses.(22-24)

Cigarette smoke contains approximately 107 oxidant molecules per puff.(25) Thus, long term smoking can lead to increased oxidative stress leading to increased formation of reactive oxygen species (ROS). This leads to a systemic imbalance in the oxidant-antioxidant status as reflected by increased products of lipid peroxidation (F2 isoprostanes and malondialdehyde), oxidized low density lipoprotein (LDL) and depleted levels of antioxidants like vitamin C, β carotene, α carotene, and α tocopherol in plasma of smokers(12). Free radicals produce DNA damage, and accumulated damages lead to somatic mutations and malignant transformation of cells. Elevated ROS levels have been implicated in a variety of other disease conditions including respiratory diseases, cataract, atherosclerosis and myocardial infarction, osteoporosis, reperfusion injury, and aging.(26) ROS promote sulphydryl-mediated cross-linking of proteins, resulting in enhanced degradation and alteration of enzyme activity, thus may affect critical signal transduction pathways. Studies in our laboratory and elsewhere in animals and humans have indicated that antioxidant phytonutrients such as those from garlic (Sallyl cysteine, S-allyl cysteine sulfoxide), onion (S-methyl cysteine sulfoxide) and flavonoids can ameliorate the deleterious effects of the toxic chemicals present in CS.(27-30)

The anticancer and cardioprotective effect of many flavonoids including isoflavones may be attributed to their antigenotoxic and antioxidant properties(31). An increased systemic inflammatory response is observed in smokers as is evident by elevated levels of C-reactive protein (CRP), fibrinogen, and interleukin-6, homocysteine, as well as increased counts of WBC.(12) The precise mechanisms linking smoking and atherogenesis, the process leading to cardiovascular disease (CVD), is complex and not fully understood. However, increased inflammation, vascular endothelial dysfunction (increased levels of soluble intracellular adhesion molecule, P-selectin, E-selectin, impairment of tissue plasminogen activator release), systemic hemostatic and coagulation disturbances (increased hematocrit and plasma viscosity, fibrin ddimer) and lipid abnormalities have been implicated as possible causes leading to CVD in smokers.(32,33)

Smoking during pregnancy holds additional risks for both the mother and foetus. Those who smoke throughout their pregnancies increase the risk of spontaneous abortion/ miscarriage, ectopic pregnancy, abruptio placentae, placenta previa, and premature rupture of the membranes, premature birth, and increased vaginal bleeding.(34) Carbon monoxide and nicotine from CS may interfere with the oxygen supply to the foetus. Nicotine also readily crosses the placenta, with concentrations in the foetus reaching as much as 15% higher than maternal levels. Nicotine concentrates in foetal blood, amniotic fluid and breast milk. Risks to the foetus include: foetal growth retardation and decreased birth weights, stillborn infant, birth defects, increased nicotine receptors in baby’s brain, attention disorders, increased likelihood of child smoking as a teenager, and possible predisposition to adult anxiety disorders.(35, 36) The antiangiogenic activities associated with exposure to total particulate matter from cigarette smoking during pregnancy can be fatal to growing embryos.(37) It can also affect the process of wound healing after surgery.(38)

The vice-like grip of smoking

Nicotine is the major psychoactive substance in tobacco that is responsible for the development and maintenance of tobacco dependence. Most smokers use tobacco regularly because they are addicted to nicotine. Nicotine binds to specific nicotinic acetlylcholine receptors (nAchR) throughout the brain and in autonomic ganglia. It also binds to receptors in the nigrostriatal and mesolimbic dopaminergic neurons. The development of nicotine dependence is thought to be linked to stimulation of the dopamine reward pathway in the midbrain.(34) Monoamine oxidase (MAO) is an important enzyme that is responsible for the breakdown of dopamine. Using advanced neuroimaging technology such as whole-body PET-scan, it has been shown that brains of tobacco smokers have a marked decrease in the levels of monoamine oxidase, which reverts to control level when they quit smoking.(39) The decrease in activity of two forms of MAO (A and B) have been reported, which may be the reason that smokers are less prone to develop Parkinson’s disease.(40,41) A few MAO inhibitors such as 2, 3, 6- trimethyl-1, 4-napthoquinone, farnesylacetone, and transfarnesol have been isolated and characterised from tobacco leaf extracts and CS.(42) The decrease in levels of MAO leads to elevated dopamine levels, and is thought to underlie the pleasurable sensations experienced by smokers. Smokers continue to smoke to sustain the high dopamine levels that lead to a craving for more. Animal studies have also revealed that acetaldehyde present in CS may also contribute to tobacco addiction. It has been suggested that acetaldehyde may increase the addictive potential of tobacco products via the formation of acetaldehyde-biogenic amines such as harman which readily passes through the blood-brain barrier and inhibit MAO. The blood harman levels in smokers appear to be 2-10 times higher compared to nonsmokers.( 43) Recent evidence suggests that individuals have genetically based differences in their ability to metabolise nicotine, as well as genetic differences in the psychological reward pathways that may influence individual response to smoking initiation, dependence, addiction and cessation.(44,45)

Understanding the pharmacogenomics of cigarette smoking can be vital for improved prevention and treatment of tobacco addiction.

Conclusions

Smoking is a ‘modern peril’ which is the single major cause of avoidable morbidity and early mortality. Cigarette smoke contains thousands of toxic chemicals that harm virtually every organ system in the body. The precise molecular mechanisms involved in pathogenesis of many of the so called smoking induced diseases still remains to be elucidated. Smoking during pregnancy is harmful both the mother and foetus. Most smokers use tobacco regularly because they are addicted to nicotine. The best way to avoid the adverse health effects of smoking is to stay away from it, or for smokers to quit the habit at the earliest.

The Authors

● Biju C Mathew* PhD, Assistant Professor, Department of Medical Biochemistry Faculty of Medicine, El Gabal El Gharby University, Gharyan, Libya * Corresponding author susanbiju_661@rediffmail.com

● Reji Susan Daniel PhD Lecturer, Department of Medical Biochemistry Faculty of Medicine, El Gabal El Gharby University, Gharyan, Libya.

● Jamal Al Bahlool BordomMD Professor, Department of Social and Preventive Medicine & Dean Faculty of Medicine, El Gabal El Gharby University, Gharyan, Libya.

● K.T.Augusti PhD Emeritus Professor, Department of Biochemsitry, School of Health Sciences, Kannur University, India

● Ian W Campbell MD FRCPE FRCP (Glasgow) Emeritus Professor of Medicine, Victoria Hospital, Bute Medical School, University of St Andrews, Scotland, United Kingdom

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ate of upload: 26th Jan 2010

                                  
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