|Year : 2015 | Volume
| Issue : 1 | Page : 24-31
Harmful effects of nicotine
Aseem Mishra, Pankaj Chaturvedi, Sourav Datta, Snita Sinukumar, Poonam Joshi, Apurva Garg
Department of Surgical Oncology, Head and Neck Services, Tata Memorial Hospital, Parel, Mumbai, Maharashtra, India
|Date of Web Publication||19-Feb-2015|
Professor Pankaj Chaturvedi
Department of Surgical Oncology, Head and Neck Services, Tata Memorial Hospital, Dr. E. Borges Road, Parel, Mumbai - 400 012, Maharashtra
Source of Support: None, Conflict of Interest: None
With the advent 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 not included nicotine as a carcinogen. However there are various studies which show otherwise. We 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 done using a combination of the keywords. All the animal and human studies investigating only the role of nicotine were included. Nicotine poses several health hazards. There is an increased risk of cardiovascular, respiratory, gastrointestinal disorders. There is decreased immune response and it also poses ill impacts on the reproductive health. It affects the cell proliferation, oxidative stress, apoptosis, DNA mutation by various mechanisms which leads to cancer. It also affects the tumor proliferation and metastasis and causes resistance to chemo and radio therapeutic agents. The use of nicotine needs regulation. The sale of nicotine should be under supervision of trained medical personnel.
Keywords: Addiction, cancer, cardiovascular, gastrointestinal, nicotine, respiratory
|How to cite this article:|
Mishra A, Chaturvedi P, Datta S, Sinukumar S, Joshi P, Garg A. Harmful effects of nicotine. Indian J Med Paediatr Oncol 2015;36:24-31
|How to cite this URL:|
Mishra A, Chaturvedi P, Datta S, Sinukumar S, Joshi P, Garg A. Harmful effects of nicotine. Indian J Med Paediatr Oncol [serial online] 2015 [cited 2017 Dec 15];36:24-31. Available from: http://www.ijmpo.org/text.asp?2015/36/1/24/151771
| 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 5.4 million deaths per year and one billion people may die in this century if global tobacco consumption remained at the current levels.  An international treaty spearheaded by WHO in 2003 and signed by 170 countries, aims to encourage governments to reduce the production, 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.  As tobacco consumption is being curbed, there is a growing demand for cessation. Pharmacological treatment of nicotine addiction remains an active area of research. There are many nicotine preparations (nicotine gums, patches, e cigarettes and inhalational agents) that are freely available in most parts of the world. 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. E-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 most countries. 
Nicotine is well known to have serious systemic side effects in addition to being highly addictive. It adversely affects the heart, reproductive system, lung, kidney etc. Many studies have consistently demonstrated its carcinogenic potential.[Table 1] The only other known use of nicotine has been as an insecticide since 17 th century.  After World War II, its use has declined owing to the availability of cheaper, more potent pesticides that are less harmful to mammals. The environment Protection Agency of United States has banned use of nicotine as a pesticide from 1 st January 2014.  India, one of the largest producer and exporter of nicotine sulphate, has progressively banned its use as agricultural pesticide.  We undertook this review to evaluate the systemic adverse effects of nicotine.
| Materials and Methods|| |
A computer aided search of the Medline and PubMed databases was done using different combination of the keywords "nicotine," "chemical composition," "history," "metabolism," "addiction," "cancer," "toxic," "endocrine system," "cardiovascular system," "respiratory system," "lung carcinogenesis, "gastrointestinal system," "immune 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 animal and human 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 look at the effects of nicotine without confounding effects of other toxins and carcinogens present in tobacco or tobacco smoke.
| 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 form is a clear liquid with a characteristic odour. It turns brown 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.  The absorption can occur through oral mucosa, lungs, skin or gut.  The increase in pH of a solution causes an increase in concentrations of uncharged lipophilic nicotine, in this form it can actively pass through all biological membranes.  The addition of slaked lime and catechu to tobacco increases the absorption 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.  This leads to formation of various metabolites like cotinine and nornicotine, demethyl cotinine, trans-3-hydroxy-cotinine and d-(3-pyridyl)-g-methylaminobutyric acid. , Thereafter in phase II there is N'-and O'-glucuronidation of the metabolites and excretion via urine, feces, bile, saliva, sweat etc. , 5-10% of elimination is by renal excretion of unchanged nicotine, however there is reabsorption from the bladder when the urinary pH is high.  There is evidence that nitrosation of nicotine in vivo could lead to formation of N-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK).  which are known to be highly carcinogenic. Inflammation in the oral cavity increases risk of endogenous nitrosation.
| Mechanism of Action|| |
Nicotine acts via 3 major mechanisms, producing physiological and pathological effects on a variety of organ systems. ,
- Ganglionic transmission.
- Nicotinic acetylcholine receptors (nAChRs) on chromaffin cells via catecholamines.
- Central nervous system (CNS) stimulation of nAChRs.
Brain imaging studies demonstrate that nicotine acutely increases activity in the prefrontal cortex and visual systems. There is release of a variety of neurotransmitters important in drug-induced reward. Nicotine also causes an increased oxidative stress and neuronal apoptosis, DNA damage, 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 system. Actions on nicotinic receptors produce a wide variety of acute and long-term effects on organ systems, cell multiplication and apoptosis, throughout the body.
| Immediate Effects and Toxicity|| |
Nicotine on direct application in humans causes irritation and burning sensation in the mouth and throat, increased salivation, nausea, abdominal pain, vomiting and diarrhea.  Gastrointestinal effects are less severe but can occur even after cutaneous and respiratory exposure.  Predominant immediate effects as seen in animal studies and in humans consist of increase in pulse rate and blood pressure. Nicotine also causes an increase in plasma free fatty acids, hyperglycemia, and an increase in the level of catecholamines in the blood. , There is reduced coronary blood flow but an increased skeletal muscle blood flow. , 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 severe poisoning, there are tremors, prostration, cyanosis, dypnoea, convulsion, progression to collapse and coma. Even death may occur from paralysis of respiratory muscles and/or central respiratory failure with a LD50 in adults of around 30-60 mg of nicotine. In children the LD50 is around 10 mg. 
| 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 acute symptoms include headache, nausea, vomiting, giddiness, loss of appetite, fatigue and tachyarrythmias.  No significant mortality has been reported due to green tobacco sickness (GTS) but it significantly affects the health of workers in the tobacco industry. 
| 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.  This in turn stimulates the reward centre and is responsible for the mood elevation and apparent improvement in cognitive function.  With chronic stimulation by nicotine the GABAergic neurons are desensitized and thus lose their inhibitory effect on dopamine.  This in turn reinforces the addiction by inducing craving. This effect has been shown to affect the CYP2A6 gene and leads to heritable dependence to nicotine. Studies have shown the nicotine dependence to be transmitted maternally and grand maternally by epigenetic mechanism. 
| Effects on Metabolism|| |
Nicotine causes catecholamine release and stimulates the autonomic system. There 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 body weight. Nicotine affects insulin resistance and predisposes to metabolic syndrome. In an animal study prenatal exposure was toxic to pancreatic β-cell and leads to decreased B cell population, thus increasing the risk of diabetes. ,
| Nicotine and Cancer|| |
The stimulation of nAChRs by nicotine has biologic effects on cells important for initiation and progression of cancer.  It activates signal transduction pathways directly through receptor-mediated events, allowing the survival of damaged epithelial cells. In addition, nicotine is a precursor of tobacco specific nitrosamines (TSNAs), through nitrosation in the oral cavity. , It is shown that nitrosation of nicotine could lead to formation of NNN and NNK. This effect of nicotine may be important because of its high concentration in tobacco and nicotine replacement products.  NNN and NNK are strongly carcinogenic. 
Nicotine forms arachidonic acid metabolites which cause increased cell division. Binding to Bcl-2 and action on vascular endothelial growth factor and cyclooxygenase-2 (COX-2) causes increased cancer proliferation and survival. , Promotion of tumor angiogenesis accelerates tumor growth which is mediated by β-adrenergic activation and stimulation of nAChRs. ,,, Nicotine also suppresses apoptosis by phosphorylation mediated extracellular signal regulated kinases of Bcl-2. , Recent studies show that nicotine, activates nuclear factor kappa B (NF-kB)-dependent survival of cancer cell and proliferation. 
In normal cells, nicotine can stimulate properties consistent with cell transformation and the early stages of cancer formation, such as increased 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 by nicotine can promote carcinogenesis by causing DNA mutations  Through its tumor promoter effects, it acts synergistically with other carcinogens from automobile exhausts or wood burning and potentially shorten the induction period of cancers  [Table 2].
| Lung Carcinogenesis|| |
A study relates lung carcinogenesis by nicotine due to genetic variation in CYP2B6.  Its simultaneous exposure with hyperoxia has been found to induce cancer in hamsters.  Cotinine has been found to promote lung tumorigenesis by inhibiting anti-apoptotic pathway.  Nuclear translocation of ARB1 gene by nicotine has found in proliferation and progression of nonsmall-cell lung cancer. Several Studies have shown that nicotine has significant role in tumor progression and metastasis via CXCR4 and increased angiogenesis. , Carriers of the lung-cancer-susceptibility loci in their DNA extract 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.  Additionally modulation of the mitochondrial signaling pathway leads to resistance to the chemotherapeutic agents. 
| Gastro Intestinal Carcinogenesis|| |
The carcinogenic role may be mediated by the MAPK/COX-2 pathways, α-7 nAchR and β-adrenergic receptor expression, and mi RNAs α-BTX anatagonist.  Nicotine forms adducts with liver DNA which enhances its mutagenic potential. ,, activation of cell-surface receptors by nicotine stimulates downstream kinases that can mediate resistance to chemotherapy. It has been shown by 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.  Nicotine affects the periostin gene, α-7-nAChR and e-cadherin suppression which explains the mechanism of gastric cancer growth, invasion and metastasis. , Nicotine negatively impacts tumor biology by promoting angiogenesis, tumor invasion and increased risk of metastasis. 
| Pancreatic Cancer|| |
Nicotine has been found to induce pancreatic adenocarcinoma in mice model, by stimulating the stress neurotransmitters. , In another study nicotine promoted the growth of nonsmall cell lung cancer and pancreatic cancer in a receptor dependent fashion. It also increased tumor metastasis, and resistance to gemcitabine induced apoptosis, causing chemoresistance.  The MUC-4 upregulation, NF-kB and GRP78 activation and Id1 expression by Src dependent manner are the probable mechanism leading to tumor growth, metastasis and chemotherapeutic drug resistance. ,
| Breast Cancer|| |
Nicotine causes α9-nAChR-mediated cyclin D3 overexpression which might cause transformation of normal breast epithelial cells and induce cancer. Nicotine and cotinine has been found to be present in the breast fluid of lactating women.  Several studies have found that α9-nAChR mediated mechanism leads to increased tumor growth, metastasis and tumor cells resistant to chemotherapeutic drugs in breast cancer. ,
| 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.  Nicotine causes catecholamine release both locally and systemically leading to an increase in heart rate, blood pressure and cardiac contractility. It reduces blood flow in cutaneous and coronary vessels; and increases blood flow in the skeletal muscles. Due to restricted myocardial oxygen delivery there is reduced cardiac work. In a study, chewing a low dose (4 mg) of nicotine gum by healthy nonsmokers blunted the increase in coronary blood flow that occurs with increased heart rate produced by cardiac pacing.  Thus, persistent stimulation by nicotine can contribute to Coronary Vascular Disease by producing acute myocardial ischemia. In the presence of coronary disease, myocardial dysfunction can be worsened. In a placebo-controlled experiment that produced transient ischemia in anesthetized dogs myocardial dysfunction was produced at doses, that did not alter heart rate, blood pressure, or blood flow or myocyte necrosis. 
Nicotine alters the structural and functional characteristics of vascular smooth muscle and endothelial cells.  It enhances release of the basic fibroblast growth factor and inhibits production of transforming growth factor-β1.  These effects lead to increased DNA synthesis, mitogenic activity, endothelial proliferation and increases atherosclerotic plaque formation.  Neovascularization stimulated by nicotine can help progression of atherosclerotic plaques.  These effects lead to myointimal thickening and atherogenic and ischemic changes, increasing the incidence of hypertension and cardiovascular disorders. A study on dogs demonstrated the deleterious effects of nicotine on the heart. 
Nicotinic acetylcholine receptor's actions on vascular smooth muscle proliferation and plaque neovascularization increases the risk of peripheral arterial disorders. In a murine model of hind limb ischemia, short-term exposure to nicotine paradoxically increased capillary density and improved regional blood flow in the ischemic hind limb.  However, long-term exposure to nicotine for 16 weeks (about one-third of the life span of a mouse) before induction of ischemia obliterated angiogenic response to nicotine. 
| 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.  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 adjacent nuclei in the brain. 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. 
| Gastrointestinal System|| |
Nicotine use has been associated with Gastro Esophageal Reflux Disorder (GERD) and peptic ulcer disease (PUD). , This effect is mediated by increased gastric acid, pepsinogen secretion and stimulatory effects on vasopressin. The action on the cyclo-oxygenase pathway also increases the risk of GERD and PUD.  Nicotine causes smooth muscle relaxation by action of endogenous nitric oxide as a nonadrenergic noncholinergic neurotransmitter.  The decrease in tone of the colon and gastric motility and reduced lower esophageal sphincteric pressure might be the reason of increased incidence of GERD. 
There is an increased incidence of treatment resistant Helicobacter pylori infection in smokers. It potentiates the effects of toxins of H. pylori by its action on the gastric parietal cells.  This effect could be due to histamine mediated response of nicotine.
| Immunological System|| |
Nicotine has been known to be immunosuppressive through central and peripheral mechanisms. It impairs antigen and receptor mediated signal transduction in the lymphoid system leading to decreased immunological response. The T-cell population is reduced due to arrest of cell cycle. Even the macrophage response, which forms the first line defense against tuberculosis becomes dysfunctional and causes increased incidence of tuberculosis.  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 as well as increased risk 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 immune system. The adrenocorticotropic hormone (ACTH) secretion pathway and corticotrophin release is affected and this causes immunosuppression. 
| Ocular System|| |
Nicotine promotes pathologic angiogenesis and retinal neovascularization in murine models. It causes age-related macular degeneration in mice.  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 age-related macular degeneration than are nonsmokers.  In animal model, spraguely Dawley rats with type 1 diabetes treated with nicotine, developed cataract.  Thus the syngergistic relationship between nicotine and glucose metabolism exaggerating diabetes might cause accelerated cataract formation. There is synergistic relationship between nicotine and glucose metabolism which increases the risk of diabetes mellitus. This might cause accelerated cataract formation.
| Renal System|| |
Risk of chronic kidney disease in smokers is high. Cigarette smoking has been found to increase albumin excretion in urine, decrease glomerular filtration rate, causes increased incidence of renal artery 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-2 isoforms causes increased glomerular inflammation, acute glomerulonephritis and ureteral obstruction.  There is impaired response of kidneys to the increased systemic blood pressure in smokers. This loss of renoprotective mechanism in smokers also leads to pathogenetic effects of nicotine on the renal system. 
| Reproductive System - Males|| |
Nitrous oxide liberated from parasympathetico-nergic nerves plays a pivotal role in generating immediate 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 lead to loss of penile erections and erectile dysfunction. 
Various animal studies suggest that nicotine causes seminiferous tubules degeneration, disrupts the spermatogenesis and at cellular level, affect germ cell structure and function in males.  It decreases testosterone levels which is secondary to decreased production of StAR.  StAR is the protein which plays an important role in testosterone biosynthesis.
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 bleeding.  There is consistent 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 effects of nicotine on the endocrine system. 
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 caused disturbed oocyte maturation. There is a decreased blood flow to the oviducts and thus impaired fertilization. 
Maternal smoking has always been known to have deleterious effects on the fetal outcome. There is an increased incidence of intrauterine growth restriction, still birth, miscarriages and mental retardation.  Various animal studies show retarded fetal growth and lower birth weight when treated perinatally with nicotine. The lower levels of ACTH and cortisol due to nicotine are probable reasons for the incidence of lower birth weight in the newborns. 
Maternal as well as grand maternal smoking has been found to increase risk of pediatric asthma. Another serious and important effect is the transgenic transmission of the addictive pattern. 
| Conclusion|| |
Nicotine is the fundamental cause of addiction among tobacco users. Nicotine adversely affects many organs as shown in human 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 found 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 substantive beneficial effect of nicotine on human body is yet to be proven. Nicotine should be used only under supervision of trained cessation personnel therefore its sale needs to be strictly regulated. Needless to say, that research for safer alternative to nicotine must be taken on priority.
| References|| |
WHO Data. Tobacco Fact Sheet; No. 339. Available from: http://www.who.int/mediacentre/factsheets/fs339/en. [Last accessed on 2015 Jan 29].
WHO Framework Convention on Tobacco Control. Available from: http://www.who.int/fctc/about/en. [Last accessed on 2014 Sep 27].
Fagerström K. The nicotine market: An attempt to estimate the nicotine intake from various sources and the total nicotine consumption in some countries. Nicotine Tob Res 2005;7:343-50.
US Environmental Protection Agency. Nicotine: Product cancellation order.Fed Regist 2009 Available from: http://www.epa.gov/fedrgstr/EPA-PEST/2009/June/Day-03/p12561.htm [Last accessed 2014 Nov 01].
APIB. Banned Pesticides. Available from: http://megapib.nic.in/Int_pest_bannedPest.htm. [Last updated on 2002 Mar 25; Last accessed on 2014 Sep 27].
Langone JJ, Gjika HB, Van Vunakis H. Nicotine and its metabolites. Radioimmunoassays for nicotine and cotinine. Biochemistry 1973;12:5025-30.
Schievelbein H, Eberhardt R, Löschenkohl K, Rahlfs V, Bedall FK. Absorption of nicotine through the oral mucosa I. Measurement of nicotine concentration in the blood after application of nicotine and total particulate matter. Inflamm Res 1973;3:254-8.
Armitage AK, Turner DM. Absorption of nicotine in cigarette and cigar smoke through the oral mucosa. Nature 1970;226:1231-2.
Sobkowiak R, Lesicki A. Absorption, metabolism and excretion of nicotine in humans. Postepy Biochem 2013;59:33-44.
Dempsey D, Tutka P, Jacob P 3 rd
, Allen F, Schoedel K, Tyndale RF, et al
. Nicotine metabolite ratio as an index of cytochrome P450 2A6 metabolic activity. Clin Pharmacol Ther 2004;76:64-72.
Nakajima M, Tanaka E, Kwon JT, Yokoi T. Characterization of nicotine and cotinine N-glucuronidations in human liver microsomes. Drug Metab Dispos 2002;30:1484-90.
Seaton MJ, Kyerematen GA, Vesell ES. Rates of excretion of cotinine, nicotine glucuronide, and 3-hydroxycotinine glucuronide in rat bile. Drug Metab Dispos 1993;21:927-32.
Stepanov I, Carmella SG, Briggs A, Hertsgaard L, Lindgren B, Hatsukami D, et al
. Presence of the carcinogen N'-nitrosonornicotine in the urine of some users of oral nicotine replacement therapy products. Cancer Res 2009;69: 8236-40.
Borzelleca JF. Drug movement from the isolated urinary bladder of the rabbit. Arch Int Pharmacodyn Ther 1965;154:40-50.
Dani JA, Ji D, Zhou FM. Synaptic plasticity and nicotine addiction. Neuron 2001;31:349-52.
Jones S, Sudweeks S, Yakel JL. Nicotinic receptors in the brain: Correlating physiology with function. Trends Neurosci 1999;22:555-61.
Smith EW, Smith KA, Maibach HI, Andersson PO, Cleary G, Wilson D. The local side effects of transdermally absorbed nicotine. Skin Pharmacol 1992;5:69-76.
Sonnenberg A, Hüsmert N. Effect of nicotine on gastric mucosal blood flow and acid secretion. Gut 1982;23:532-5.
Benowitz NL. Nicotine and smokeless tobacco. CA Cancer J Clin 1988;38:244-7.
Dani JA, Heinemann S. Molecular and cellular aspects of nicotine abuse. Neuron 1996;16:905-8.
Kaijser L, Berglund B. Effect of nicotine on coronary blood-flow in man. Clin Physiol 1985;5:541-52.
Jolma CD, Samson RA, Klewer SE, Donnerstein RL, Goldberg SJ. Acute cardiac effects of nicotine in healthy young adults. Echocardiography 2002;19:443-8.
Centre for Disease Control and Prevention. Available from: http://www.cdc.gov/niosh/idlh/54115.html. [Last accessed on 2014 Sep 27].
Parikh JR, Gokani VN, Doctor PB, Kulkarni PK, Shah AR, Saiyed HN. Acute and chronic health effects due to green tobacco exposure in agricultural workers. Am J Ind Med 2005;47:494-9.
Weizenecker R, Deal WB. Tobacco cropper's sickness. J Fla Med Assoc 1970;57:13-4.
US Department of Health and Human Services. Mental Health. Available from: http://www.samhsa.gov/data/2k12/ MHUS2010/MHUS-2010.pdf. [Last accessed on 2014 Sep 27].
Mansvelder HD, McGehee DS. Cellular and synaptic mechanisms of nicotine addiction. J Neurobiol 2002;53:606-17.
Vezina P, McGehee DS, Green WN. Exposure to nicotine and sensitization of nicotine-induced behaviors. Prog Neuropsychopharmacol Biol Psychiatry 2007;31:1625-38.
Leslie FM. Multigenerational epigenetic effects of nicotine on lung function. BMC Med 2013;11:27.
Bruin JE, Kellenberger LD, Gerstein HC, Morrison KM, Holloway AC. Fetal and neonatal nicotine exposure and postnatal glucose homeostasis: Identifying critical windows of exposure. J Endocrinol 2007;194:171-8.
Somm E, Schwitzgebel VM, Vauthay DM, Camm EJ, Chen CY, Giacobino JP, et al
. Prenatal nicotine exposure alters early pancreatic islet and adipose tissue development with consequences on the control of body weight and glucose metabolism later in life. Endocrinology 2008;149:6289-99.
IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Tobacco smoke and involuntary smoking. IARC Monogr Eval Carcinog Risks Hum 2004;83:1-1438.
Hoffmann D, Adams JD. Carcinogenic tobacco-specific N-nitrosamines in snuff and in the saliva of snuff dippers. Cancer Res 1981;41(11 Pt 1):4305-8.
International Agency for Research on Cancer. Tobacco smoke and involuntary smoking. IARC Monogr Eval Carcinog Risk Hum 2007;89:455-7.
Heeschen C, Jang JJ, Weis M, Pathak A, Kaji S, Hu RS, et al
. Nicotine stimulates angiogenesis and promotes tumor growth and atherosclerosis. Nat Med 2001;7:833-9.
Shin VY, Wu WK, Chu KM, Wong HP, Lam EK, Tai EK, et al
. Nicotine induces cyclooxygenase-2 and vascular endothelial growth factor receptor-2 in association with tumor-associated invasion and angiogenesis in gastric cancer. Mol Cancer Res 2005;3:607-15.
Natori T, Sata M, Washida M, Hirata Y, Nagai R, Makuuchi M. Nicotine enhances neovascularization and promotes tumor growth. Mol Cells 2003;16:143-6.
Wong HP, Yu L, Lam EK, Tai EK, Wu WK, Cho CH. Nicotine promotes colon tumor growth and angiogenesis through beta-adrenergic activation. Toxicol Sci 2007;97:279-87.
Zhu BQ, Heeschen C, Sievers RE, Karliner JS, Parmley WW, Glantz SA, et al
. Second hand smoke stimulates tumor angiogenesis and growth. Cancer Cell 2003;4:191-6.
Heusch WL, Maneckjee R. Signalling pathways involved in nicotine regulation of apoptosis of human lung cancer cells. Carcinogenesis 1998;19:551-6.
Mai H, May WS, Gao F, Jin Z, Deng X. A functional role for nicotine in Bcl2 phosphorylation and suppression of apoptosis. J Biol Chem 2003;278:1886-91.
Tsurutani J, Castillo SS, Brognard J, Granville CA, Zhang C, Gills JJ, et al
. Tobacco components stimulate Akt-dependent proliferation and NFkappaB-dependent survival in lung cancer cells. Carcinogenesis 2005;26:1182-95.
Slotkin TA, Seidler FJ, Spindel ER. Prenatal nicotine exposure in rhesus monkeys compromises development of brainstem and cardiac monoamine pathways involved in perinatal adaptation and sudden infant death syndrome: Amelioration by vitamin C. Neurotoxicol Teratol 2011;33:431-4.
Wassenaar CA, Dong Q, Amos CI, Spitz MR, Tyndale RF. Pilot study of CYP2B6 genetic variation to explore the contribution of nitrosamine activation to lung carcinogenesis. Int J Mol Sci 2013;14:8381-92.
Schuller HM, McGavin MD, Orloff M, Riechert A, Porter B. Simultaneous exposure to nicotine and hyperoxia causes tumors in hamsters. Lab Invest 1995;73:448-56.
Nakada T, Kiyotani K, Iwano S, Uno T, Yokohira M, Yamakawa K, et al
. Lung tumorigenesis promoted by anti-apoptotic effects of cotinine, a nicotine metabolite through activation of PI3K/Akt pathway. J Toxicol Sci 2012;37: 555-63.
Improgo MR, Soll LG, Tapper AR, Gardner PD. Nicotinic acetylcholine receptors mediate lung cancer growth. Front Physiol 2013;4:251.
Le Marchand L, Derby KS, Murphy SE, Hecht SS, Hatsukami D, Carmella SG, et al
. Smokers with the CHRNA lung cancer-associated variants are exposed to higher levels of nicotine equivalents and a carcinogenic tobacco-specific nitrosamine. Cancer Res 2008;68:9137-40.
Zhang D, Ma QY, Hu HT, Zhang M. β2-adrenergic antagonists suppress pancreatic cancer cell invasion by inhibiting CREB, NFkB and AP-1. Cancer Biol Ther 2010;10:19-29.
Jensen K, Afroze S, Munshi MK, Guerrier M, Glaser SS. Mechanisms for nicotine in the development and progression of gastrointestinal cancers. Transl Gastrointest Cancer 2012;1:81-87.
Pérez-Sayáns M, Somoza-Martín JM, Barros-Angueira F, Diz PG, Gándara Rey JM, García-García A. Beta-adrenergic receptors in cancer: Therapeutic implications. Oncol Res 2010;19:45-54.
Majidi M, Al-Wadei HA, Takahashi T, Schuller HM. Nongenomic beta estrogen receptors enhance beta1 adrenergic signaling induced by the nicotine-derived carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in human small airway epithelial cells. Cancer Res 2007;67:6863-71.
Petros WP, Younis IR, Ford JN, Weed SA. Effects of tobacco smoking and nicotine on cancer treatment. Pharmacotherapy 2012;32:920-31.
Liu Y, Liu BA. Enhanced proliferation, invasion, and epithelial-mesenchymal transition of nicotine-promoted gastric cancer by periostin. World J Gastroenterol 2011;17:2674-80.
Lien YC, Wang W, Kuo LJ, Liu JJ, Wei PL, Ho YS, et al
. Nicotine promotes cell migration through alpha7 nicotinic acetylcholine receptor in gastric cancer cells. Ann Surg Oncol 2011;18:2671-9.
Al-Wadei HA, Plummer HK 3 rd
, Schuller HM. Nicotine stimulates pancreatic cancer xenografts by systemic increase in stress neurotransmitters and suppression of the inhibitory neurotransmitter gamma-aminobutyric acid. Carcinogenesis 2009;30:506-11.
Crowley-Weber CL, Dvorakova K, Crowley C, Bernstein H, Bernstein C, Garewal H, et al
. Nicotine increases oxidative stress, activates NF-kB and GRP78, induces apoptosis and sensitizes cells to genotoxic/xenobiotic stresses by a multiple stress inducer, deoxycholate: Relevance to colon carcinogenesis. Chem Biol Interact 2003;145:53-66.
Treviño JG, Pillai S, Kunigal S, Singh S, Fulp WJ, Centeno BA, et al
. Nicotine induces inhibitor of differentiation-1 in a Src-dependent pathway promoting metastasis and chemoresistance in pancreatic adenocarcinoma. Neoplasia 2012;14:1102-14.
Chen CS, Lee CH, Hsieh CD, Ho CT, Pan MH, Huang CS, et al
. Nicotine-induced human breast cancer cell proliferation attenuated by garcinol through down-regulation of the nicotinic receptor and cyclin D3 proteins. Breast Cancer Res Treat 2011;125:73-87.
Nishioka T, Kim HS, Luo LY, Huang Y, Guo J, Chen CY. Sensitization of epithelial growth factor receptors by nicotine exposure to promote breast cancer cell growth. Breast Cancer Res 2011;13:R113.
Porchet HC, Benowitz NL, Sheiner LB, Copeland JR. Apparent tolerance to the acute effect of nicotine results in part from distribution kinetics. J Clin Invest 1987;80:1466-71.
Przyklenk K. Nicotine exacerbates postischemic contractile dysfunction of 'stunned' myocardium in the canine model. Possible role of free radicals. Circulation 1994;89:1272-81.
Csonka E, Somogyi A, Augustin J, Haberbosch W, Schettler G, Jellinek H. The effect of nicotine on cultured cells of vascular origin. Virchows Arch A Pathol Anat Histopathol 1985;407:441-7.
Villablanca AC. Nicotine stimulates DNA synthesis and proliferation in vascular endothelial cells in vitro
. J Appl Physiol. 1998;84:2089-98.
Chalon S, Moreno H Jr, Benowitz NL, Hoffman BB, Blaschke TF. Nicotine impairs endothelium-dependent dilatation in human veins in vivo
. Clin Pharmacol Ther 2000;67:391-7.
Lee J, Cooke JP. The role of nicotine in the pathogenesis of atherosclerosis. Atherosclerosis 2011;215:281-3.
Sridharan MR, Flowers NC, Hand RC, Hand JW, Horan LG. Effect of various regimens of chronic and acute nicotine exposure on myocardial infarct size in the dog. Am J Cardiol 1985;55:1407-11.
Konishi H, Wu J, Cooke JP. Chronic exposure to nicotine impairs cholinergic angiogenesis. Vasc Med 2010;15:47-54.
Beck ER, Taylor RF, Lee LY, Frazier DT. Bronchoconstriction and apnea induced by cigarette smoke: Nicotine dose dependence. Lung 1986;164:293-301.
Jaiswal SJ, Pilarski JQ, Harrison CM, Fregosi RF. Developmental nicotine exposure alters AMPA neurotransmission in the hypoglossal motor nucleus and pre-Botzinger complex of neonatal rats. J Neurosci 2013;33:2616-25.
Chu KM, Cho CH, Shin VY. Nicotine and gastrointestinal disorders: Its role in ulceration and cancer development. Curr Pharm Des 2013;19:5-10.
Ogle CW, Qiu BS, Cho CH. Nicotine and gastric ulcers in stress. J Physiol Paris 1993;87:359-65.
Irie K, Muraki T, Furukawa K, Nomoto T. L-NG-nitro-arginine inhibits nicotine-induced relaxation of isolated rat duodenum. Eur J Pharmacol 1991;202:285-8.
Kadakia SC, De La Baume HR, Shaffer RT. Effects of transdermal nicotine on lower esophageal sphincter and esophageal motility. Dig Dis Sci 1996;41:2130-4.
Endoh K, Leung FW. Effects of smoking and nicotine on the gastric mucosa: A review of clinical and experimental evidence. Gastroenterology 1994;107:864-78.
Geng Y, Savage SM, Johnson LJ, Seagrave J, Sopori ML. Effects of nicotine on the immune response. I. Chronic exposure to nicotine impairs antigen receptor-mediated signal transduction in lymphocytes. Toxicol Appl Pharmacol 1995;135:268-78.
Sopori ML, Kozak W, Savage SM, Geng Y, Soszynski D, Kluger MJ, et al
. Effect of nicotine on the immune system: Possible regulation of immune responses by central and peripheral mechanisms. Psychoneuroendocrinology 1998;23:189-204.
Suñer IJ, Espinosa-Heidmann DG, Marin-Castano ME, Hernandez EP, Pereira-Simon S, Cousins SW. Nicotine increases size and severity of experimental choroidal neovascularization. Invest Ophthalmol Vis Sci 2004;45:311-7.
Seddon JM, Willett WC, Speizer FE, Hankinson SE. A prospective study of cigarette smoking and age-related macular degeneration in women. JAMA 1996;276:1141-6.
Tirgan N, Kulp GA, Gupta P, Boretsky A, Wiraszka TA, Godley B, et al
. Nicotine exposure exacerbates development of cataracts in a type 1 diabetic rat model. Exp Diabetes Res 2012;2012:349320.
Jaimes EA, Tian RX, Joshi MS, Raij L. Nicotine augments glomerular injury in a rat model of acute nephritis. Am J Nephrol 2009;29:319-26.
Halimi JM, Philippon C, Mimran A. Contrasting renal effects of nicotine in smokers and non-smokers. Nephrol Dial Transplant 1998;13:940-4.
Xie Y, Garban H, Ng C, Rajfer J, Gonzalez-Cadavid NF. Effect of long-term passive smoking on erectile function and penile nitric oxide synthase in the rat. J Urol 1997;157:1121-6.
Jana K, Samanta PK, De DK. Nicotine diminishes testicular gametogenesis, steroidogenesis, and steroidogenic acute regulatory protein expression in adult albino rats: Possible influence on pituitary gonadotropins and alteration of testicular antioxidant status. Toxicol Sci 2010;116:647-59.
Oyeyipo IP, Raji Y, Bolarinwa AF. Nicotine alters male reproductive hormones in male albino rats: The role of cessation. J Hum Reprod Sci 2013;6:40-4.
Jin Z, Roomans GM. Effects of nicotine on the uterine epithelium studied by X-ray microanalysis. J Submicrosc Cytol Pathol 1997;29:179-86.
Hammer RE, Mitchell JA, Goldman H. Effects of nicotine on concept us cell proliferation and oviductal/uterine blood flow in the rat. In: Cellular and Molecular Aspects of Implantation. US: Springer; 1981. p. 439-42.
Chen M, Wang T, Liao ZX, Pan XL, Feng YH, Wang H. Nicotine-induced prenatal overexposure to maternal glucocorticoid and intrauterine growth retardation in rat. Exp Toxicol Pathol 2007;59:245-51.
Liu L, Liu F, Kou H, Zhang BJ, Xu D, Chen B, et al
. Prenatal nicotine exposure induced a hypothalamic-pituitary-adrenal axis-associated neuroendocrine metabolic programmed alteration in intrauterine growth retardation offspring rats. Toxicol Lett 2012;214:307-13.
[Table 1], [Table 2]