A review on tobacco and its effect on health

Contact us: sciencevision@outlook.com Tobacco is an important agricultural product that is consumed all over the world. More than 8000 chemicals are reported to be present in tobacco, and a large number of these chemicals are known carcinogens, and hence is known to be one of the most significant contributors to the development of cancer of different body parts. These chemicals have been reported to alter both the genetic and epigenetic constituents of cells. Such changes involve point mutation, deletion, insertion, recombination, transversion, transition, and chromosomal aberrations including aneuploidy and polyploidy. The chemical composition of different types of tobacco has been reported to be different. In this article, brief information about tobacco plants; history, types and popularity of tobacco; its chemical composition; relation to cancer and other diseases and its effects on the molecular, epigenetic and genetic compositions have been highlighted.


Introduction
Tobacco is an important agricultural product processed from the plant of the genus Nicotiana belonging to the family Solanaceae. 1 There are 72 known species of Nicotiana, however, N. tabacum and N. rustica are of major economic importance as they are consumed in various forms. 2 Tobacco plants are known to prosper in tropical and subtropical climatic conditions and are either cultivated or found in the wild. The body of a tobacco plant consists of a hollow, spongy stem and is mostly one to two meters tall depending on the species and variety. The leaves are covered by minute viscid glandular hairs and the plants mostly thrive in moist soil and humid environment. Any part of the plant is processed into other products for consumption. These products are referred to as tobacco while the plant is referred to as a tobacco plant. The method of processing and consumption varies considerably throughout the world. It is consumed singly or in combination with other ingredients. 3 Volume 19 | Issue 1 | January-March 2019 www.sciencevision.org Tobacco consumption is popular all over the world. In fact, every nation throughout the world is a nation with tobacco users in its population. 7 It is estimated that there are approximately 1 billion men and 250 million women who used tobacco globally. [8][9][10] As a general consequence, an individual's habit of consuming any form of tobacco is an influence of peers or popular culture. Most tobacco users started the practice during adolescent or early adulthood. During the early stage of usage, users claimed to have pleasurable sensations which served as a positive reinforcement. This positive reinforcement gradually compelled the users to be habituated to it. This habituation is an effect of nicotine, a powerful addictive chemical in the tobacco. Once the users are habituated to tobacco, or more specifically nicotine, they found it exceptionally challenging to discontinue its consumption. The discontinuance of tobacco consumption by habituated users leads to withdrawal symptoms, which include anxiety, restlessness, irritability, shortened attention span and intense craving for tobacco or nicotine. 11 Although nicotine is non-carcinogenic, 12-14 its effect on the physiological and psychological construct of the body is immense, with elevation of heart rate, blood pressure, cardiac output and oxygen consumption; relaxed the musculo-skeletal dynamics and cognizance; increased alertness and brought euphoria to the users. It also decreases muscular strength and lowers anaerobic performance. Nicotine has also been reported to have damaging effect on DNA of cultured epithelial and non-epithelial human cells. 15

Types of Tobacco
The kind of tobacco and its associated products used worldwide vary considerably from place to place and also depend upon the choice of the individual consumers. The choice of tobacco used often reflects the socio-economic status of the users. Certain tobacco products are rather expensive and their consumptions, in a way, reflect the users' luxurious way of life. The availability of such tobacco products is also an important factor in the users' selection for consumption. Generally, tobacco can be divided into two types, smoking (combustible) and smokeless (non-combustible) tobacco. Smoking is the most common practice of tobacco consumption all over the world and consists of great number of varieties. Every cultures and communities have different specific names or brands for the smoked tobacco products. Some of the most popular varieties include cigarette, cigar, pipe, hookah, bidi, cheroot, cigarillos, little cigar, kreteks, etc. Smoked tobacco products are initially hand rolled, but after the industrial revolution, factories and industries took over its production and is currently one of the biggest industries. 18,19 Smokeless tobaccos are another form of consumable tobacco product. Many smokeless tobaccos are either sun-dried or fire-dried and are mostly orally consumed, although some are nasally used. There also exist liquid form of tobacco in the north eastern part of India. 20,21 Some of the popular smokeless tobaccos include chewing tobacco, tuibur or hidakphu (tobacco brew), snuff, khaini, raja, mawa, mishri, snus, betel nut quid, spit tobacco, gutkha, tiranga, shikhar, hogesoppu, kaddipudi, gundi, kiwam, zarda, pattiwala, mainpuri, kharra, bajjar, gul, gudakhu, naswar, etc. The means of consumption of these tobaccos vary greatly; some are ingested while others are simply kept in the mouth and spitted out after some time. 22-24

Chemical Composition of Tobacco
Tobacco is known to contain more than 8000 chemicals, out of which more than 80 have probable carcinogenic properties. [25][26][27][28][29] The soil on which a tobacco plant grows plays a significant role in determining some of the chemicals found in the plant. The plant often absorbs toxic chemicals from the soil along with other nutrients and water and stores it in certain parts of their structure. Therefore, the type and number of chemicals vary among different types of tobacco products. 30 Some of the common toxic chemicals found in tobacco include benzo[a]pyrene, N'-nitrosonornicotine (NNN), N'nitrosoanatabine (NAT), N'-nitrosoanabasine (NAB), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), N-nitrosodimethylamine (NDMA), nitrite, cadmium, lead, arsenic, nickel, chromium, isoprene, styrene, acrylonitrile, acetaldehyde, formaldehyde, polonium-210, benzene, p-cresol, p-benzoquinone, N-nitrosodiethylamine, ethylenethiourea, chrysene, , mercury, zinc, copper, nicotine, etc. [31][32][33][34] Many of these chemicals exhibit toxic, cytotoxic, genotoxic, mutagenic, teratogenic and carcinogenic properties and some of them are classified under class I carcinogens. The types of chemicals present in smoked and smokeless tobaccos also differ. Many chemicals are synthesized during the burning/ pyrolysis of the tobacco in the process of smoking. [35][36][37][38][39] In fact, every smoked and smokeless tobacco will have different chemical constituents depending on the method of processing and geographical area of the crop production. 40,41 A study on the chemical composition of the tar phase of tuibur, a locally manufactured tobacco brew by the Mizos showed the presence of mainly non-polar organic substances that may be described as semi-volatile and nonvolatile. 42

TOBACCO AND CANCER
Although the Native Americans were known to use tobacco as medicine, its detrimental effects on health came to light in the mid-19 th century. From then onwards, the injurious health effect of tobacco has been recorded thousands of times from all over the world. As some of the chemicals of tobacco are carcinogenic, the consumption of tobacco has been associated with many forms of cancer. 33,43-47 In fact, almost all known cancers can be correlated to tobacco consumption. However, the most direct involvement of cancer can be seen in cancer of the mouth, lungs, esophagus, stomach, liver, pharynx, colon, etc. 48-50 Some epidemiological studies had shown that smoke and smokeless tobacco increased the risk of gastric cancer. 21,51 Smoking tobacco alone has also been reported to increase the risk of developing lung cancer. 52 Individuals having GSTM1 null genotype and GSTT1 non-null genotype with the habit of using tobacco were shown to have a higher risk of developing gastric cancer. 53 Many studies have shown that individuals smoking a pack of cigarette per day showed 50% increase in colon cancer than non-smokers and even those who discontinued smoking remained at increased risk for the development of cancer, even if they stopped the habit very early. Contrastingly, some studies have established a protective effect for terminated smoking. The amount an individual smoked may have been a more important factor than the duration of smoking in the development of cancer. The consumption of alcohol in addition to tobacco has also been found to significantly increase the risk of colon cancer. 54-56 Tobacco smoking, alcohol consumption and betel quid chewing have been observed to significantly increase the risk of lung cancer. 57-58 Lung, laryngeal and pharyngeal cancers have highest relative risk in current smokers than former smokers. 59 Smokeless tobacco has also been attributed to increase the risk of many tobacco related cancers. 23,60,61

IN OTHER DISEASES
Besides cancer, it has also been known to cause several diseases mostly involving the pulmonary system like bronchitis, asthma, tuberculosis, laryngitis, pharyngitis, etc. and autoimmune rheumatic diseases. 62-66 Tobacco not only causes cancer deaths but is also responsible for great number ofdeaths from cardiovascular, chronic obstructive pulmonary and degenerative diseases. [67][68][69] In 2000, 4.83 million premature deaths worldwide were attributed to tobacco use, of which 2.41 million were in developing and 2.43 million in developed industrialized countries and these numbers are expected to increase up to 10 million a year by 2030. 9, 70 The use of tobacco has also been known to cause adversities in pregnancy outcomes, possibly leading to abortion. 71,72 Some studies estimated that tobacco use will result in an annual death exceeding approximately 12 million and each year 6.7 million new tobacco related cancer cases diagnosed. 8,73

MOLECULAR EFFECTS OF TOBACCO
Tobacco has been known to affect both the genetic and epigenetic components of the cell, thus resulting in abnormal cell proliferation and apoptosis; upregulation of certain oncogenes and inhibition and down regulation of tumour suppressor genes. The genetic effects may be in the form of point mutation, deletion, insertion, recombination, transversion, transition, and chromosomal aberrations including aneuploidy and polyploidy. These gross changes lead to the overexpression or inactivation of certain key cancer related genes. 74,75 The epigenetic effects include hypermethylation of CpG islands in the promoter region of tumour suppressor genes, hypomethylation in the promoter region of protooncogenes, acetylation, phosphorylation, ubiquitylation, sumoylation, ribosylation and citrullination of some amino acids of the histone proteins. These changes affect the structure and ultimately the function of DNA, thereby leading to abnormal cellular functions and eventually leading to cancer. [76][77][78] The mechanism of action of DNA damage caused by tobacco involved variety of pathways. One pathway involves oxidative stress caused by highly reactive compounds called free radicals. 79,80 These free radicals were formed within the cell or can come from external source such as tobacco tar. Free radicals present in tobacco tar had been found to penetrate viable cells, bound to DNA and produce nicks in the DNA, thus altering the DNA structure. [81][82][83] Tobacco is a rich source of oxidants and thus depletes the antioxidants of the body causing increase oxidative stress. This oxidative stress had been observed to damage sperms. The spermatozoa of smokers had been found to have a significantly higher level of DNA fragmentation, DNA strand break and 8-OHdG DNA adducts than non-smokers. 9, [84][85][86] Other studies had also shown that smoking reduced sperm production and motility. However, some reported smoking to have a negative impact on intracellular antioxidants but did not necessarily increase oxidative DNA damage. 87,88 In a study involving bladder cancer patients, 4aminobiphenyl-DNA adducts were higher in current smokers than ex-smokers. 89,90 One of the carcinogens present in tobacco, NNK had been found to alter the structure of XRCC1, a DNA repair protein, therefore decreasing the protein's ability to repair damaged DNA. 91 One of the most important tumour suppressor genes, p53 had been known to be negatively affected by the use of tobacco in many studies. In head and neck squamous cell carcinoma, p53 and cyclin D1, cell cycle checkpoint genes were found to be mutated and over expressed. [92][93][94] In non-small cell lung cancer, exposure to tobacco carcinogens caused mutation in p53, EGFR, hMLH1, FHIT, hMSH3 and D9S157 loci. Majority of these mutations were deletion of a single base pair or more, thus, resulting in loss of heterozygosity. [95][96][97][98] Among lung cancer patients with history of tobacco use and none at all, the pattern of mutation differed. It was found that there was an excess of guanine to thymine transversions in smoking related lung cancers. This G to T transversion was 30% prevalent in smokers while it was only 12% among the non-smokers. 99 Smokers were also found to have higher number of small chromatid exchanges. 100 Besides smoking tobacco, the use of smokeless tobacco also demonstrated many genetic alterations between tobacco users and non-users. p53, p21, Kras, Bax, IL-6, TNF-α, iNOS and Cox-2 genes were found to be highly expressed among smokeless tobacco users, whereas Bcl-2 (an important apoptotic gene) expression seemed to decrease. [101][102][103] However, some studies did not find any correlation between tobacco use and mutations in important genes including H-ras, EGRF, K-ras, p53 and Cox-2. 92