What can nicotine use lead to over time?
Indian J Med Paediatr Oncol. 2015 Jan-Mar; 36(1): 24–31.
Harmful effects of nicotine
Aseem Mishra
Department of Surgical Oncology, Head and Neck Services, Tata Memorial Hospital, Parel, Bombay, Maharashtra, India
Pankaj Chaturvedi
Department of Surgical Oncology, Caput and Neck Services, Tata Memorial Hospital, Parel, Mumbai, Maharashtra, India
Sourav Datta
Section of Surgical Oncology, Head and Neck Services, Tata Memorial Hospital, Parel, Mumbai, Maharashtra, Republic of india
Snita Sinukumar
Department of Surgical Oncology, Head and Neck Services, Tata Memorial Hospital, Parel, Bombay, Maharashtra, Bharat
Poonam Joshi
Department of Surgical Oncology, Head and Neck Services, Tata Memorial Infirmary, Parel, Bombay, Maharashtra, India
Apurva Garg
Department of Surgical Oncology, Head and Neck Services, Tata Memorial Hospital, Parel, Mumbai, Maharashtra, India
Abstract
With the appearance of nicotine replacement therapy, the consumption of the nicotine is on the rise. Nicotine is considered to be a safer alternative of tobacco. The IARC monograph has non included nicotine as a carcinogen. However there are diverse studies which show otherwise. Nosotros undertook this review to specifically evaluate the effects of nicotine on the various organ systems. A computer aided search of the Medline and PubMed database was washed using a combination of the keywords. All the animate being and human being studies investigating only the function of nicotine were included. Nicotine poses several wellness hazards. There is an increased run a risk of cardiovascular, respiratory, gastrointestinal disorders. There is decreased immune response and it as well poses ill impacts on the reproductive health. It affects the prison cell proliferation, oxidative stress, apoptosis, Dna mutation by diverse mechanisms which leads to cancer. It also affects the tumor proliferation and metastasis and causes resistance to chemo and radio therapeutic agents. The utilize of nicotine needs regulation. The sale of nicotine should be under supervision of trained medical personnel.
Keywords: Addiction, cancer, cardiovascular, gastrointestinal, nicotine, respiratory
INTRODUCTION
Tobacco is the leading cause of preventable cancers. WHO estimated around 1.27 billion tobacco users world-wide. Tobacco consumption alone accounts for nearly five.iv one thousand thousand deaths per yr and 1 billion people may dice in this century if global tobacco consumption remained at the current levels.[i] An international treaty spearheaded past WHO in 2003 and signed by 170 countries, aims to encourage governments to reduce the product, sales, distribution advertisement and promotion of tobacco products. Despite strong opposition from the Industry, the treaty has been making steady progress in achieving its goal of comprehensive tobacco control around the world.[2] As tobacco consumption is existence curbed, there is a growing demand for cessation. Pharmacological treatment of nicotine habit remains an active area of research. In that location are many nicotine preparations (nicotine gums, patches, due east cigarettes and inhalational agents) that are freely bachelor in almost parts of the globe. These products are being heavily promoted and marketed as magical remedies. Nicotine gums are available in 2 mg and 4 mg preparation that deliver around 1 mg and 3 mg nicotine to the blood stream respectively. Due east-cigarette, a sophisticated nicotine delivery device, delivers nicotine in a vapor form and it closely mimics the act of smoking. Currently, these products constitute approximately 1% of total nicotine consumption and are showing an increasing trend in well-nigh countries.[3]
Nicotine is well known to take serious systemic side furnishings in addition to beingness highly addictive. It adversely affects the center, reproductive system, lung, kidney etc. Many studies have consistently demonstrated its carcinogenic potential. [Table 1] The just other known use of nicotine has been as an insecticide since 17th century.[four] Afterward Globe State of war II, its apply has declined owing to the availability of cheaper, more strong pesticides that are less harmful to mammals. The surround Protection Bureau of The states has banned apply of nicotine as a pesticide from 1st January 2014.[iv] Bharat, one of the largest producer and exporter of nicotine sulphate, has progressively banned its use as agronomical pesticide.[v] We undertook this review to evaluate the systemic adverse effects of nicotine.
Table 1
Studies showing nicotine as a carcinogen
MATERIALS AND METHODS
A computer aided search of the Medline and PubMed databases was washed using different combination of the keywords "nicotine," "chemical composition," "history," "metabolism," "addiction," "cancer," "toxic," "endocrine system," "cardiovascular arrangement," "respiratory system," "lung carcinogenesis, "gastrointestinal system," "allowed system," "ocular," "cataract," "central nervous system," "renal system," "reproductive system," "menstrual cycle," "oocytes," "foetus,". Initial search buildup was done using "Nicotine/adverse effects" [Mesh], which showed 3436 articles. Articles were analyzed and 90 relevant articles were included in the review. All the fauna and man studies that investigated the role of nicotine on organ systems were analyzed. Studies that evaluated tobacco use and smoking were excluded. All possible physiological effects were considered for this review. We did not exclude studies that reported beneficial effects of nicotine. The objective was to wait at the furnishings of nicotine without confounding effects of other toxins and carcinogens present in tobacco or tobacco fume.
CHEMICAL PROPERTIES AND METABOLISM
Nicotine was first extracted from tobacco by German physicians Wilhelm Heinrich Posselt and Karl Ludwig Reimann. Nicotine, a strong alkaloid, in its pure class is a clear liquid with a characteristic odour. It turns brownish on exposure to air. It is water soluble and separates preferentially from organic solvents. It is an amine composed of pyridine and pyrrolidine rings.
Nicotine is a dibasic compound and the availability and absorption in human body depends upon the pH of the solution.[7] The absorption tin occur through oral mucosa, lungs, skin or gut.[6] The increase in pH of a solution causes an increase in concentrations of uncharged lipophilic nicotine, in this form it can actively laissez passer through all biological membranes.[7] The add-on of slaked lime and catechu to tobacco increases the assimilation of nicotine from the oral cavity.
Nicotine once ingested, is absorbed and metabolized by the liver. The metabolic process can be categorized into two phases. In phase I there is microsomal oxidation of the nicotine via multiple pathways.[8] This leads to germination of diverse metabolites like cotinine and nornicotine, demethyl cotinine, trans-three-hydroxy-cotinine and d-(three-pyridyl)-m-methylaminobutyric acid.[9,10] Thereafter in phase Two at that place is N'-and O'-glucuronidation of the metabolites and excretion via urine, feces, bile, saliva, sweat etc.[11,12]5-ten% of elimination is past renal excretion of unchanged nicotine, however there is reabsorption from the float when the urinary pH is high.[fourteen] There is show that nitrosation of nicotine in vivo could lead to germination of N-nitrosonornicotine (NNN) and iv-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK).[13] which are known to be highly carcinogenic. Inflammation in the mouth increases hazard of endogenous nitrosation.
Machinery OF ACTION
Nicotine acts via three major mechanisms, producing physiological and pathological effects on a variety of organ systems.[15,16]
-
Ganglionic transmission.
-
Nicotinic acetylcholine receptors (nAChRs) on chromaffin cells via catecholamines.
-
Central nervous system (CNS) stimulation of nAChRs.
Encephalon imaging studies demonstrate that nicotine acutely increases activeness in the prefrontal cortex and visual systems. At that place is release of a variety of neurotransmitters important in drug-induced reward. Nicotine besides causes an increased oxidative stress and neuronal apoptosis, Dna harm, reactive oxygen species and lipid peroxide increase. nAChRs were originally thought to be limited to neuronal cells, however, studies have identified functional nAChRs in tissues outside the nervous organisation. Actions on nicotinic receptors produce a wide diverseness of acute and long-term effects on organ systems, cell multiplication and apoptosis, throughout the body.
Firsthand EFFECTS AND TOXICITY
Nicotine on direct application in humans causes irritation and burning sensation in the oral fissure and throat, increased salivation, nausea, abdominal pain, vomiting and diarrhea.[17] Gastrointestinal furnishings are less severe but tin occur even after cutaneous and respiratory exposure.[xviii] Predominant immediate effects as seen in animal studies and in humans consist of increase in pulse charge per unit and claret pressure. Nicotine also causes an increase in plasma free fatty acids, hyperglycemia, and an increase in the level of catecholamines in the blood.[19,20] There is reduced coronary blood flow but an increased skeletal muscle blood catamenia.[20,22] The increased rate of respiration causes hypothermia, a hypercoagulable state, decreases skin temperature, and increases the blood viscosity.
Nicotine is one of the most toxic of all poisons and has a rapid onset of action. Apart from local actions, the target organs are the peripheral and central nervous systems. In astringent poisoning, at that place are tremors, prostration, cyanosis, dypnoea, convulsion, progression to collapse and coma. Even death may occur from paralysis of respiratory muscles and/or fundamental respiratory failure with a LD50 in adults of effectually 30-60 mg of nicotine. In children the LD50 is around 10 mg.[23]
GREEN TOBACCO SICKNESS
This is an acute form of nicotine toxicity that is known to occur due to handling of green tobacco leaves, with symptoms lasting from 12 to 24 h. The astute symptoms include headache, nausea, vomiting, giddiness, loss of appetite, fatigue and tachyarrythmias.[24] No significant bloodshed has been reported due to greenish tobacco sickness (GTS) merely it significantly affects the health of workers in the tobacco industry.[25]
NICOTINE Addiction
Nicotine is one of the most addicting agent. The Us surgeon general (2010) has concluded nicotine to be as addictive as cocaine or heroin. Nicotine interacts with the nicotinic acetyl choline receptors and stimulates the dopaminergic transmission.[26] This in turn stimulates the advantage heart and is responsible for the mood elevation and apparent improvement in cognitive function.[27] With chronic stimulation by nicotine the GABAergic neurons are desensitized and thus lose their inhibitory effect on dopamine.[28] This in turn reinforces the habit by inducing craving. This effect has been shown to touch on the CYP2A6 gene and leads to heritable dependence to nicotine. Studies take shown the nicotine dependence to exist transmitted maternally and yard maternally by epigenetic mechanism.[29]
Effects ON METABOLISM
Nicotine causes catecholamine release and stimulates the autonomic organisation. In that location is increased glycogen synthesis due to α-adrenoceptor stimulation. This leads to reduction in the fasting blood glucose levels. It also causes lipolysis thus decreasing torso weight. Nicotine affects insulin resistance and predisposes to metabolic syndrome. In an creature study prenatal exposure was toxic to pancreatic β-jail cell and leads to decreased B jail cell population, thus increasing the risk of diabetes.[xxx,31]
NICOTINE AND CANCER
The stimulation of nAChRs by nicotine has biologic effects on cells important for initiation and progression of cancer.[26] Information technology activates signal transduction pathways straight through receptor-mediated events, allowing the survival of damaged epithelial cells. In add-on, nicotine is a precursor of tobacco specific nitrosamines (TSNAs), through nitrosation in the oral cavity.[32,33] It is shown that nitrosation of nicotine could lead to germination of NNN and NNK. This effect of nicotine may exist important considering of its high concentration in tobacco and nicotine replacement products.[thirteen] NNN and NNK are strongly carcinogenic.[34]
Nicotine forms arachidonic acrid metabolites which cause increased prison cell division. Binding to Bcl-2 and action on vascular endothelial growth factor and cyclooxygenase-2 (COX-2) causes increased cancer proliferation and survival.[35,36] Promotion of tumor angiogenesis accelerates tumor growth which is mediated past β-adrenergic activation and stimulation of nAChRs.[35,37,28,39] Nicotine too suppresses apoptosis past phosphorylation mediated extracellular point regulated kinases of Bcl-two.[forty,41] Contempo studies show that nicotine, activates nuclear factor kappa B (NF-kB)-dependent survival of cancer cell and proliferation.[42]
In normal cells, nicotine can stimulate properties consistent with cell transformation and the early on stages of cancer formation, such as increased jail cell proliferation, decreased cellular dependence on the extracellular matrix for survival, and decreased contact inhibition. Thus, the induced activation of nAChRs in lung and other tissues past nicotine can promote carcinogenesis by causing DNA mutations[26] Through its tumor promoter effects, it acts synergistically with other carcinogens from automobile exhausts or wood burning and potentially shorten the consecration catamenia of cancers[43] [Table 2].
Table 2
Studies showing the function of nicotine as tumor promoter
LUNG CARCINOGENESIS
A written report relates lung carcinogenesis by nicotine due to genetic variation in CYP2B6.[44] Its simultaneous exposure with hyperoxia has been establish to induce cancer in hamsters.[45] Cotinine has been found to promote lung tumorigenesis by inhibiting anti-apoptotic pathway.[46] Nuclear translocation of ARB1 factor by nicotine has establish in proliferation and progression of nonsmall-cell lung cancer. Several Studies accept shown that nicotine has significant function in tumor progression and metastasis via CXCR4 and increased angiogenesis.[36,47] Carriers of the lung-cancer-susceptibility loci in their Deoxyribonucleic acid excerpt more nicotine. Smokers carrying the gene CHRNA3 and CHRNA5 were found to extract more nicotine and cells were thus exposed to a higher internal dose of carcinogenic nicotine-derived nitrosamines.[48] Additionally modulation of the mitochondrial signaling pathway leads to resistance to the chemotherapeutic agents.[49]
GASTRO Intestinal CARCINOGENESIS
The carcinogenic role may exist mediated by the MAPK/COX-two pathways, α-7 nAchR and β-adrenergic receptor expression, and mi RNAs α-BTX anatagonist.[l] Nicotine forms adducts with liver Dna which enhances its mutagenic potential.[49,51,52] activation of cell-surface receptors by nicotine stimulates downstream kinases that can mediate resistance to chemotherapy. It has been shown past the finding that smokers who continue to smoke during chemotherapy have a worse prognosis. Moreover they also have increased toxicity and lower efficacy of chemo therapeutic drugs.[53] Nicotine affects the periostin gene, α-7-nAChR and e-cadherin suppression which explains the machinery of gastric cancer growth, invasion and metastasis.[54,55] Nicotine negatively impacts tumor biology by promoting angiogenesis, tumor invasion and increased risk of metastasis.[53]
PANCREATIC CANCER
Nicotine has been found to induce pancreatic adenocarcinoma in mice model, past stimulating the stress neurotransmitters.[56,57] In another study nicotine promoted the growth of nonsmall prison cell lung cancer and pancreatic cancer in a receptor dependent fashion. Information technology as well increased tumor metastasis, and resistance to gemcitabine induced apoptosis, causing chemoresistance.[58] The MUC-4 upregulation, NF-kB and GRP78 activation and Id1 expression by Src dependent style are the likely mechanism leading to tumor growth, metastasis and chemotherapeutic drug resistance.[57,58]
BREAST CANCER
Nicotine causes α9-nAChR-mediated cyclin D3 overexpression which might cause transformation of normal chest epithelial cells and induce cancer. Nicotine and cotinine has been found to be nowadays in the breast fluid of lactating women.[59] Several studies have constitute that α9-nAChR mediated mechanism leads to increased tumor growth, metastasis and tumor cells resistant to chemotherapeutic drugs in breast cancer.[59,60]
CARDIOVASCULAR SYSTEM
The acute hemodynamic effects of cigarette smoking or smokeless tobacco are mediated primarily by the sympathomimetic action. The intensity of its hemodynamic effect is greater with rapid nicotine delivery.[61] Nicotine causes catecholamine release both locally and systemically leading to an increase in eye rate, blood pressure and cardiac contractility. It reduces claret flow in cutaneous and coronary vessels; and increases blood flow in the skeletal muscles. Due to restricted myocardial oxygen delivery in that location is reduced cardiac piece of work. In a study, chewing a low dose (4 mg) of nicotine gum past healthy nonsmokers blunted the increment in coronary blood flow that occurs with increased heart charge per unit produced past cardiac pacing.[21] Thus, persistent stimulation by nicotine can contribute to Coronary Vascular Illness by producing acute myocardial ischemia. In the presence of coronary disease, myocardial dysfunction can exist worsened. In a placebo-controlled experiment that produced transient ischemia in anesthetized dogs myocardial dysfunction was produced at doses, that did not change centre rate, claret pressure, or blood catamenia or myocyte necrosis.[62]
Nicotine alters the structural and functional characteristics of vascular polish muscle and endothelial cells.[63] It enhances release of the basic fibroblast growth factor and inhibits product of transforming growth gene-β1.[64] These furnishings atomic number 82 to increased Dna synthesis, mitogenic activity, endothelial proliferation and increases atherosclerotic plaque formation.[65] Neovascularization stimulated past nicotine can assistance progression of atherosclerotic plaques.[66] These effects pb to myointimal thickening and atherogenic and ischemic changes, increasing the incidence of hypertension and cardiovascular disorders. A report on dogs demonstrated the deleterious effects of nicotine on the heart.[67]
Nicotinic acetylcholine receptor's actions on vascular shine muscle proliferation and plaque neovascularization increases the take chances of peripheral arterial disorders. In a murine model of hind limb ischemia, short-term exposure to nicotine paradoxically increased capillary density and improved regional claret flow in the ischemic hind limb.[35] However, long-term exposure to nicotine for 16 weeks (nigh one-third of the life span of a mouse) earlier induction of ischemia obliterated angiogenic response to nicotine.[68]
RESPIRATORY SYSTEM
The effects of nicotine on respiratory system are twofold. One, directly by a local exposure of lungs to nicotine through smoking or inhaled nicotine, and second via a central nervous system mechanism. Nicotine plays a role in the development of emphysema in smokers, by decreasing elastin in the lung parenchyma and increasing the alveolar volume. Nicotine stimulates vagal reflex and parasympathetic ganglia and causes an increased airway resistance by causing bronchoconstriction.[69] Nicotine alters respiration through its effects on the CNS. The simultaneous effect of bronchoconstriction and apnea increases the tracheal tension and causes several respiratory disorders. In a study microinjection of nicotine were administered to the prebotzinger complex and side by side nuclei in the encephalon. The firing pattern of the brain signals and breathing pattern were monitored. There was an increased frequency of bursts and decreased amplitude and a shallow and rapid rhythm of respiration.[70]
GASTROINTESTINAL Organization
Nicotine use has been associated with Gastro Esophageal Reflux Disorder (GERD) and peptic ulcer illness (PUD).[36,71] This upshot is mediated by increased gastric acrid, pepsinogen secretion and stimulatory effects on vasopressin. The action on the cyclo-oxygenase pathway also increases the risk of GERD and PUD.[72] Nicotine causes polish muscle relaxation by action of endogenous nitric oxide as a nonadrenergic noncholinergic neurotransmitter.[73] The subtract in tone of the colon and gastric move and reduced lower esophageal sphincteric pressure might be the reason of increased incidence of GERD.[74]
There is an increased incidence of treatment resistant Helicobacter pylori infection in smokers. Information technology potentiates the effects of toxins of H. pylori past its action on the gastric parietal cells.[75] This event could exist due to histamine mediated response of nicotine.
IMMUNOLOGICAL Organization
Nicotine has been known to be immunosuppressive through central and peripheral mechanisms. It impairs antigen and receptor mediated betoken transduction in the lymphoid system leading to decreased immunological response. The T-cell population is reduced due to arrest of cell wheel. Fifty-fifty the macrophage response, which forms the first line defense confronting tuberculosis becomes dysfunctional and causes increased incidence of tuberculosis.[76] The migration of fibroblasts and inflammatory cells to the inflamed site is reduced. There is decreased epithelialization and cell adhesion and thus there is a delayed wound healing also equally increased take a chance of infection in nicotine exposed individuals.
The action on the hypothalamo-pituitary adrenal axis and autonomic nervous system stimulation via sympathetic and parasympathetic pathways affects the allowed system. The adrenocorticotropic hormone (ACTH) secretion pathway and corticotrophin release is affected and this causes immunosuppression.[77]
OCULAR Organization
Nicotine promotes pathologic angiogenesis and retinal neovascularization in murine models. Information technology causes age-related macular degeneration in mice.[78] In a clinical study, the most virulent form of age-related maculopathy was associated with retinal neovascularization that contributed to visual deterioration. Tobacco smokers are known to be at greater risk of historic period-related macular degeneration than are nonsmokers.[79] In animal model, spraguely Dawley rats with blazon 1 diabetes treated with nicotine, developed cataract.[80] Thus the syngergistic relationship between nicotine and glucose metabolism exaggerating diabetes might cause accelerated cataract formation. There is synergistic relationship betwixt nicotine and glucose metabolism which increases the risk of diabetes mellitus. This might cause accelerated cataract formation.
RENAL SYSTEM
Risk of chronic kidney affliction in smokers is high. Cigarette smoking has been found to increase albumin excretion in urine, decrease glomerular filtration rate, causes increased incidence of renal avenue stenosis and is associated with an increased mortality in patients with end-stage renal disease. The pathogenesis of renal effects is due to the action of nicotine via COX-2 isoform induction. The COX-ii isoforms causes increased glomerular inflammation, astute glomerulonephritis and ureteral obstacle.[81] There is dumb response of kidneys to the increased systemic blood force per unit area in smokers. This loss of renoprotective machinery in smokers also leads to pathogenetic effects of nicotine on the renal system.[82]
REPRODUCTIVE System – MALES
Nitrous oxide liberated from parasympathetico-nergic nerves plays a pivotal role in generating firsthand penile vasodilatation and corpus cavernosum relaxation, and NO derived from endothelial cells contributes to maintaining penile erection. Nicotine causes impairment of NO synthesis. This may atomic number 82 to loss of penile erections and erectile dysfunction.[83]
Diverse animal studies suggest that nicotine causes seminiferous tubules degeneration, disrupts the spermatogenesis and at cellular level, impact germ cell construction and function in males.[84] It decreases testosterone levels which is secondary to decreased production of StAR.[85] StAR is the protein which plays an of import role in testosterone biosynthesis.
REPRODUCTIVE SYSTEM – Female person
Menstrual cycle
Nicotine by inhibiting the 21 hydoxylase causes hypoestrogenic state. It shunts the metabolites to formation of androgen. This leads to chronic anovulation and irregular menstrual cycles. Nicotine can predispose the endometrium to inappropriate cytokine production and irregular haemorrhage.[86] At that place is consequent evidence that increase in follicle-stimulating hormone levels and decreases in estrogen and progesterone that are associated with cigarette smoking in women, is atleast in part due to furnishings of nicotine on the endocrine system.[26]
Effect on oocytes
Nicotine affects the ovaries and alters the production of oocytes in various animal studies. Nicotine-treated oocytes appeared nonspherical with rough surface and torn and irregular zona-pellucida. Nicotine also acquired disturbed oocyte maturation. There is a decreased blood catamenia to the oviducts and thus impaired fertilization.[87]
Peri-natal effects
Maternal smoking has always been known to accept deleterious effects on the fetal outcome. There is an increased incidence of intrauterine growth restriction, nonetheless nativity, miscarriages and mental retardation.[88] Various animate being studies bear witness retarded fetal growth and lower birth weight when treated perinatally with nicotine. The lower levels of ACTH and cortisol due to nicotine are likely reasons for the incidence of lower nascency weight in the newborns.[89]
Maternal every bit well as one thousand maternal smoking has been found to increase risk of pediatric asthma. Another serious and important effect is the transgenic manual of the addictive pattern.[29]
Decision
Nicotine is the central cause of addiction among tobacco users. Nicotine adversely affects many organs as shown in human being and animal studies. Its biological effects are widespread and extend to all systems of the body including cardiovascular, respiratory, renal and reproductive systems. Nicotine has also been constitute to be carcinogenic in several studies. It promotes tumorigenesis by affecting cell proliferation, angiogenesis and apoptotic pathways. It causes resistance to the chemotherapeutic agents. Nicotine replacement therapy (NRT) is an effective adjunct in management of withdrawal symptoms and improves the success of cessation programs. Any noun beneficial effect of nicotine on homo torso is nonetheless to be proven. Nicotine should be used only under supervision of trained cessation personnel therefore its auction needs to exist strictly regulated. Needless to say, that research for safer alternative to nicotine must be taken on priority.
Footnotes
Source of Support: Nil
Conflict of Interest: None declared.
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