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International Journal of Biochemistry & Physiology Research Article 47 min read

A Mechanistic Review of Nicotine Toxicity with Recent Updates

Zahra A*
* Corresponding author
ISSN: 2577-4360  10.23880/ijbp-16000155  Received: March 15, 2019  Published: April 19, 2019
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 228 references
 2 figures
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Keywords
Nicotine Reactive oxygen species Toxicity Organs Systems
Abstract

There are concerns about the spread of cigarette smoking and nicotine is the most harmful agent in cigarette smoke. The statics show the growing use of cigarette smoking. Nicotine is an alkaloid and is present in the leaves of tobacco where it acts as a botanical insecticide. It represents 90% of total alkaloid in cigarette smoke. Osteoporosis, lung and kidney injuries, diseases of respiratory and cardiovascular systems, and increased risk of malignancy are just a few of toxic effects of nicotine on the body. Nicotine exerts its harmful effects via oxidative stress pathway, so that it enhances the production of reactive oxygen species (ROS) and then negatively affects different organs and systems of body. This review provides a comprehensive review of detrimental effects of nicotine on the body and then describes its mechanism of toxicity.

Introduction

During recent years much attention has been performed towards the toxicity of compound and finding naturally occurring agents for overcoming their toxicity and nicotine is one of the toxic agents [1, 2, 3, 4, 5, 6]. Nicotine has harmful effects on health and its using is increasing [7]. The mortality from cigarette smoking is approximately 178000 women in United States, so that lung cancer, heart disease and chronic lung disease are three causes of death in smoking women [8]. Surprisingly, more than 90% of smokers are interested in quitting and almost one in three try cessation each year [9, 10]. The first few weeks after cessation, nicotine withdrawal syndrome is most intense and creates difficult condition and that is the reason of short-living cessation [11, 12]. The most harmful compound that is found in the cigarette smoke, is nicotine [13]. Nicotine is present in the leaves of tobacco where it has role as a botanical insecticide (Figure 1) [14, 15]. A medium tobacco rod has 10 to 14 mg of nicotine and during smoking, 1 to 1.5 mg of nicotine is systematically absorbed [16, 17]. The nicotine in tobacco is mostly in the form of levorotary (S)-isomer and a little part (0.1 to 0.6%) of whole nicotine content is (R)-nicotine [18]. Because of using plant-derived nicotine, chemical reagents and pharmaceutical formulations of (S)-nicotine have a similar content of (R)-nicotine [18]. Due to occurring racemization during combustion, it has been reported that more than 10% of nicotine in smoke is (R)- isomer [19, 20]. In this review, we investigate the adverse impacts of nicotine on different organs and systems of body and then, explain its mechanism of toxicity.

Figure 1: The structure of nicotine (C10H14N2).
Click to enlarge
Figure 1: The structure of nicotine (C10H14N2).

Effects on Liver

During the smoking, nicotine is absorbed via lungs and is immediately metabolized in liver and then, exerts three major harmful effects on the liver: toxic (direct or indirect), immunological and oncogenic [21, 22, 23, 24]. The harmful effects of nicotine on the liver include histopathological alterations, changes in the serum level of enzymes showing liver activity (such as aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP)), alterations in the antioxidant enzymes of liver tissue and serum level of nitric oxide (NO). Elevated diameter of hepatocytes and central vein [23], accumulation of lipids and steatosis in the liver [24] are histopathological changes resulting from nicotine exposure. These changes are maybe due to the increased metabolic activity of cells for removing toxins from body during the toxification process [25]. AST and ALT are involved in the gluconeogenesis and aminoacid metabolism. They function in a pyridoxal phosphate (PLP)-dependent manner. Besides, they accelerate the metabolism of glucose and proteins. Liver metabolic syndrome, atherogenesis and type I and II diabetes can increase the activity of these enzymes [26, 27, 28, 29, 30]. Similarly, nicotine increases the level of AST and ALT [23, 31] demonstrating the increased activity of liver that maybe again is due to eliminating this toxic agent. ALP plays a significant role in the metabolism of phosphate and also catalyzes the dephosphorylation of proteins, nucleic acids and different small molecules. It is a biomarker of liver diseases [32]. It has been shown that nicotine administration increases the level of ALP [23, 21]. Furthermore, ALP serves as a biomarker of cellular adjustment to the various injuring factors [33, 34]. Increased level of NO is another adverse effect of nicotine usage. The secretion and release of noradrenaline in paraventricular nucleus and amygdale via a direct impact on the nuclei of solitary tract and N-methyl-D aspartate are triggered by nicotine that subsequently induces the generation of NO and neuronal noradrenergic activity [35]. Nicotine can increase the serum levels of cholesterol, triglyceride, LDL and VLDL. Furthermore, it diminishes the levels of HDL [36]. The levels of superoxide dismutase (SOD), catalase (CAT), glutathione-reductase (GSH) and glutathione-peroxidase enzymes of liver tissue decrease at the result of nicotine exposing demonstrating the decreased level of antioxidant capacity of liver [36].

Effects on Bone

Bone is one of the strong connective and high specialized tissues composed of organic and inorganic elements [37, 38, 39, 40, 41]. Changes in the physical and physiological conditions lead to the different functions of specialized cells in bone. Osteoblasts, osteoclasts and osteocytes are specialized cells of bone which respectively involve in the formation, resorption and remodeling of bone [42]. As well as increased risk of malignancy, osteoporosis and diseases of respiratory and cardiovascular systems are adverse effects of nicotine on the body (43-48), nicotine affects negatively the wound healing and fracture repair [49, 50, 51, 52, 53, 54, 55, 56, 57, 58]. Decreased bone mineral density, diminished blood supply, decreased number of bone forming cells and increased absorption of carbon monoxide are factors that cause skeletal defects [59, 60]. The initial inflammatory response, soft callus formation, hard callus formation and bone remodeling are four steps of bone healing [61]. Cytokines, growth factors, prosteogenic and angiogenic factors, inflammatory cells, vascular cells, osteochondral progenitors and osteoclasts adjust these four events [61, 62, 63, 64, 65]. Naturally, any agent that disturbs one of the mentioned factors, can produce defects in bone. It has been shown that men who start smoking in young adulthood, have poorer development in their areal bone mineral density compared to the nonsmokers [66]. Also, the risk of hip fracture is higher in both male and female smokers [67]. Liang et al investigated the impacts of nicotine on the rat primary osteoblasts [68]. Their data showed that nicotine remarkably reduces the proliferation of osteoblasts. Besides, nicotine elevates the activity of alkaline phosphatase (ALP). Similarly, Fang et al demonstrated that nicotine has inhibitory effects on the cellular proliferation and stimulatory effects on ALP activity in a dose-dependent manner in rat osteoblastic osteosarcoma cells [69]. Also, nicotine stimulates apoptosis in osteoblasts [70].

Effects on the Kidney

After the absorption of nicotine, it circulates in the body and rapidly distributes in different tissues. Most of the nicotine is metabolized by liver. Also, kidneys and lungs are involved in the metabolism of nicotine [71]. Nicotine results in the activation of cytochrome P-450 dependent monooxygenases in the liver. Then, the cotinine is formed that is considered as an important marker of nicotine intake [72]. Eliminating the cotinine produced by the liver is performed by kidney. Oxidative stress is the major pathway that nicotine uses to stimulate its harmful effects on the kidney [73]. Nicotine increases the generation of reactive oxygen species (ROS) resulting in the DNA damage, cancer, heart diseases, brain dysfunction and progression of ageing process [74]. Due to the increasing usage of cigarette, the injuries in the renal are increasing [75].

The increased serum levels of urea and creatinine are considered as the markers of renal injury [76]. Nicotine leads to the increased serum levels of urea and creatinine [77]. Acute renal injuries, dilation and destroying the cells lining proximal and distal convoluted tubules are the major histopathological changes of kidney caused by nicotine [78]. Lipid peroxidation is an important contributor of the loss of cell function under oxidative stress conditions [79]. This condition might lead to the renal injury. Increased level of malondialdehyde (MDA) and decreased level of GST and GSH have been reported in the kidney of rats exposed to the nicotine.

Another way that nicotine uses to produce kidney injury, is inflammation. Exposing to nicotine stimulates macrophages to release pro-inflammatory mediators. Then, they activate neutrophils to synthesize free radicals, elastase and inflammatory cytokines including TNF- - 6 and IL-1b [80]. It has been shown that inflammatory cytokines have an important role in the development and progression of chronic renal failure (CRF) [81]. Zahran and Emam [77] demonstrated that exposing to the nicotine is associated with increased concentrations of mentioned cytokines. NF-kB network has a role in inflammatory, autoimmune and malignant disorders [82]. It is a transcription factor which activates different inflammatory genes, resulting in cellular damage [83]. The increased level of ROS stimulates the generation of inflammatory cytokines, resulting in the activation of NF- kB signaling mechanism [84]. The activation of NF-kB leads to the transcription of several genes such as IL-6, TGF-B1 and VEGF. Next, the proteins produce NO by promotion of inducible nitric oxide synthase (iNOS) gene, synthesize free radicals and activate apoptosis via caspase resulting in the kidney injury [85]. Janus and coworkers [86] showed that nicotine stimulates apoptosis by activation of caspase 3 via induction of NF-kB signaling mechanism. There are findings about the elevated level of protein expression of NF-kB, caspase-3 and NO [77]. Chattopadhyay and coworkers [36] mentioned similar results about the effects of nicotine on the kidney.

Effects on the Lung

Although lungs have a major role in the absorption of nicotine, this organ has not been extensively studied. There are evidences about the role of nicotine in increasing the proliferation of non-small cell lung cancer (NSCLC). Xuemei and coworkers [87] investigated this role of nicotine. They showed that nicotine increases the proliferation of NSCLC cell via nicotine-miR 99b/miR- 192-FGF R3/R1 regulatory network. It has been shown that nicotine (as an addictive component of tobacco smoke), is not able to begin tumorigenesis in humans and rodents [88], but it can increase the growth and metastasis of different tumors such as lung cancer. This phenomenon is the result of stimulation of cell-cycle progression, angiogenesis and epithelial-mesenchymal transition (EMT) [89, 90, 91]. Furthermore, the promotion of EMT, invasion and migration of NSCLC cells have been reported at the result of exposing to the nicotine which are through regulating STMN-3 and GSPT1 genes in an ID1-dependent manner [92]. A similar study also has demonstrated the role of nicotine in the promotion of growth and metastasis of lung cancer in mouse xenograft models [93].

Nicotine increases the proliferation of lung tumor cells via binding to the nicotine acetylcholine receptors (nAChRs). These receptors are pentameric ligand-gated ion channels that located on the membranes of different cells in lung tumor cells. Nicotine is the agonist of nAChR that through binding, stimulates a change in the conformation of nAChR. This conformation change provides the influx of sodium and calcium ions. Then, the calcium-dependent and calcium-independent downstream signaling pathways of nAChR are activated. It has been demonstrated that induction of these signaling pathways might result in the proliferative and anti- apoptotic actions of nicotine [91, 94, 96].

The lungs of newborn rats exposed to maternal nicotine have been studied [97]. Emphysema, increased interstitial tissue, increased number of alveolar macrophages and mast cells are histopathological changes. Also, biochemical analysis showed the increased level of MDA and decreased level of GSH at the result of exposing to nicotine.

Effects on the Nervous System

A preventable risk factor for stroke is cigarette smoking and smoking-ingested nicotine deteriorates post-stroke brain damage [98, 99]. Nicotine is rapidly transported from blood to brain because it is used as a cerebral blood flow marker [100, 101, 102], so nicotine can cross the blood-brain barrier (BBB). Nicotine has analgesic and antinoceptive properties, so that it can decrease the post-operative pain scores in non-smokers and also reduces the consumption of morphine [103, 104]. In neurons, conformational change and influx of sodium and calcium ions at the result of binding of nicotine to the nAChR, result in the depolarization of the cell and initiation of action potential.

Aromatase enzyme catalyzes the conversion of androgens into estrogens and nicotine inhibits its function [105]. Due to the involvement of estrogen receptor-beta (ER-β) in the estrogen-mediated neuroprotection and its role in the regulation of inflammasome [106, 107, 108], so decreased level of ER- β increases the inflammasome activation. Adesky and coworkers showed that exposing to the nicotine reduces the levels of ER-β protein [109]. Also, they showed that nicotine elevates the activation of inflammasome in the brain, so that it increases the protein levels of caspase 1, ASC and IL-1β.

Amygdala is a part of the mesocorticolimbic dopamine systems and is involved in the association of discrete stimuli with drugs of addiction [110]. It has been shown that the activities of amygdala and related regions including anterior cingulate cortex (ACC) and the orbitofrontal cortex (OFC) have increased in smokers [111, 112, 113, 114, 115]. Recently, Shen and coworkers [116] investigated the function of amygdala at the result of exposing to the nicotine. They reported the elevated activity of amygdala in the right hemisphere, but the activity of left amygdala was similar to non-smokers.

It has been reported that there is a relationship between nicotine exposure and the level of nerve growth factor (NGF). Exposing to the nicotine upregulates the NGF mRNA in embryo spinal cord neurons and its receptors in PC12 cell line [117, 118, 119]. The mechanism of releasing NGF is interesting. Airway structural cells and inflammatory cells infiltered in the bronchial mucosa physiologically release NGF [120, 121, 122]. It has been shown that exposing to the nicotine stimulates NGF release in lung fibroblasts and also elevates the levels of NGF in lung homogenates and BAL fluid [123, 124]. Recently, Stabile and coworkers [125] demonstrated more obvious the relationship between nicotine usage and NGF receptors in bronchial epithelial cell line.

Developmental nicotine exposure results in the alterations in cholinergic and nervous system [126, 127, 128, 129, 130, 131, 132, 133]. Furthermore, prenatal nicotine exposure results in the differences in brain size, and changes in dendrite, spines and specific regions of central nervous system (CNS) [134, 135, 136]. Dopamine plays a remarkable role in the normal development of nervous system. It has been shown that prenatal nicotine exposure alters the dopamine release [137, 138, 139, 140, 141, 142, 143, 144], so regardless of increased or decreased level of dopamine, nervous system might not have an ordinary development. Recently, Morris and coworkers [145] studied the developmental nicotine exposure on the nervous system of Drosophila melanogaster larvae. They demonstrated alterations in the dopaminergic system, brain area, TH levels and number of TH+ neurons.

The Effects on the Reproductive System

Infertility is a major health problem with harmful impacts on various psychological, social, personal and economic aspects [146]. Male factors are responsible for 50% of infertility cases. There is a relationship between smoking and infertility in men [147, 148]. Decreased gametogenesis and steroidogenesis, and inhibited secretion of gonadotropin hormones are the results of nicotine usage [149]. Also, exposing to nicotine decreases testosterone release [150, 151, 152], estradiol [153, 154], follicle-stimulating hormone (FSH) and luteinizing hormone (LH) [149]. The number, movement, survival and normal morphology of sperms are negatively affected by nicotine [155, 156]. Besides, nicotine decreases the weight of testes, body and libido [151, 155]. It has been reported that nicotine usage elevates apoptosis in reproductive system [157, 158]. Other researches also mentioned nicotine as a factor of causing infertility because of its adverse effects on the sperm count, motility, morphology, viability and testicular weight [159, 160].

Nicotine has inhibitory effects on the CNS, so that it can prevent neural stimulus essential for the release of gonadotropins from hypophysis [161]. Also, spermatogenesis is a highly controlled process and its regulation is based on the testosterone and gonadotropins such as LH and FSH [162]. Recently, Mohammadghasemi and Jahromi demonstrated that nicotine remarkably diminishes the levels of LH and testosterone [163], so impaired spermatogenesis could be an obvious result of nicotine exposure. Also, nicotine increases the level of testicular lipid peroxidation and decreases the level of testicular antioxidant [155].

To assess more accurately the fertility status, the evaluation of sperm DNA is recommended [162]. Decreased fertility is associated to the high levels of sperm DNA damage [162]. Also, oxidative stress is known as a factor of producing single- and double-strand deoxyribunucleic acid (DNA) breaks [164, 165]. Recently, Mohammadghasemi and Jahromi [163] showed that exposing to nicotine interrupts the unity of sperm chromatin. Also, nicotine enhances the generation of cholesterol, triglycerides, phospholipids and free fatty acids in the testes and enhances peroxidative damage [166].

Blood-testis barrier (BTB) is an important structure of the seminiferous epithelium that is constituted by sertoli cells. The tight junctions, desmosomes, gap junctions and basal ectoplasmic specializations reinforce this barrier [167, 168]. Solute carrier transporters (SLC22A) are a type of influx transporters which are involved in nicotine transport system [169]. Recently, Das and coworkers [170] showed the downregulation of SLC22A at the result of exposing to the nicotine that demonstrates the attempt of testis for preventing the influx of nicotine into the testis.

What is obvious is the spread of smoking habit in young men which results in the disruption of pubertal development of Leydig cells. The development of Leydig cells is controlled by the hypothalamus-pituitary axis. Hypothalamus synthesizes gonadotrophin-releasing hormone that binds to its receptor in the pituitary and induces the secretion of LH and FSH. These two hormones have a significant role in directly or indirectly stimulating Leydig cell development [171, 172]. Guo and coworkers [173] showed the decreased concentration of LH and FSH in rats exposing to nicotine. Also, as we mentioned, nicotine binds to nAChRs and exerts its effects. These receptors are mainly distributed in plant ganglion, adrenal medulla, skeletal muscle, neuromuscular junction and brain [174]. Ge, et al. [175] and Favaretto, et al. [176] confirmed the existence of nAChRs on the Leydig cells of rats.

The prevalence of smoking has increased among the women in Europe and USA [177, 178]. The association between decreased fertility and smoking is not well known. Due to inhibition of aromatase enzyme activity by nicotine, the conversion of androgens into estrogens does not happen, so decreased level of estrogen and early onset of menopause in women are the results of nicotine exposure [179, 180, 181, 182, 183, 184, 185, 186, 187]. Nicotine disrupts the relationship between acetylcholine and its receptor and exerts its detrimental effects on placenta. This interruption results in adverse effects on blood flow, amniotic flow and transfer of nutrients. Also, it is harmful for the development of placental bed [188]. Nicotine leads to the early abortion via harmfully affecting embryo adherence to endometrium [189].

A properly prepared endometrium is necessary for the embryo implantation and quality of endometrium has a remarkable role in occurrence and continuation of pregnancy. It has been reported that the implantation rates are lower in smokers compared to the nonsmokers [190]. There are controversial results about the uterine receptivity rates of smokers and non-smokers. In a research, for evaluation of uterine receptivity in in vitro fertilization (IVF) cycles, three groups of patients provided: non-smokers, light smokers (smoking less than 10 cigarettes a day) and heavy smokers (smoking more than 10 cigarettes a day). It has been shown that the implantation rate significantly decreased at heavy smokers, but there was no difference at non-smokers and light smokers [191]. It has been demonstrated that high levels of cotinine (metabolite of nicotine) in follicular fluid is associated with higher rate of implantation failure and decreased number of live births [189].

Maternal levels of oestriol, oestradiol, human chorionic gonadotropin (hCG), human placental lactogen (hPL) and placental aromatase activity decrease in the smokers. Besides, nicotine prevents regeneration of human embryonic stem cells and binding of active adhesion molecules [192]. These effects might result in the inhibited invasion of trophoblast and unfavorable pregnancy outcomes.

Nicotine usage changes the transportation of ions in uterine fluid and epithelium [193] affecting hatching and outgrowth of blastocytes [194]. Also, it disrupts endometrial decidualization [195], prolongs gestation, prevents cervical ripening [196] and degenerates endometrium in the uterus and ovarian follicles in female rats [197]. Halder and coworkers [198] investigated the histological profile of uterine in rats exposed to nicotine. They showed decreased height of luminar epithelium, decomposition of basal layer, unregularly distribution of cells in luminar epithelium, decreased diameter of lumen in uterine glands and unregularly distribution of cells and vacuoles in glandular epithelium.

Epidemiologically, cigarette smoking is a main risk for tubal ectopic pregnancy. Animal and human researches demonstrated the effects of nicotine exposure on oviduct/fallopian tube function [199, 200].

It seems that the ovarian reserve is lower in smokers. Nicotine increases the number of atretic follicles and decreases the number of corpora lutea in female rats treated with nicotine [201, 202]. Also, it prevents the release of gonadotropins from pituitary that results in atrophy of gonadal structure and function [203]. Besides, nicotine can act directly on the ovarian morphology [202].

Effects on the Cardiovascular and Hematopoietic Systems

Cigarette smoking is considered as one of the major causes of premature cardiovascular disease (CVD) [204, 205]. Increased plasma level of epinephrine, elevated cardiac work, myocardial contractility and increased blood pressure are the results of cigarette smoking [204]. Due to the impacts of nicotine on the $$ \mathrm {E} = \frac {1}{2} \mathrm {A} ^ {2} + \mathrm {B} ^ {2} $$ -adrenergic receptors, the diameter of coronary arteries decreases and subsequently, coronary blood flow decreases. Also, nicotine has ischemia and arrhythmogenic effects, resulting in increased risk of sudden cardiac death in smokers compared to the non- smokers. Besides, nicotine increases the blood pressure, but in regular smokers, there is no relationship between cigarette smoking and high blood pressure. Flouris and coworkers [206] showed that adolescents who smoke, are at the higher risk of CVD. Also, it has been reported that adolescents are more vulnerable compared to the adults [207, 208, 209].

CV health mainly depends on the vascular endothelium. Early atherosclerotic lesions result from endothelial dysfunction [210, 211]. It has been demonstrated that endothelial cells are important targets of inflammatory cytokines which release from different immune and vascular cells [212]. Tumor necrosis factor $$ \mathrm {E} = \mathrm {E} _ {1} + \mathrm {E} _ {2} + \dots + \mathrm {E} _ {n} $$ stimulates endothelial nitric oxide dysfunction, ROS generation and proliferation of vascular smooth muscle cell, leading to the endothelial dysfunction and increased risk of CVDs [115, 213, 214]. Liu and coworkers [215] showed that nicotine usage enhances endothelial dysfunction, vascular oxidative stress and vascular inflammation.

Organ or systemMajor adverse effects
Liver• Increased diameter of hepatocytes and central vein
• Increased level of ALP, ALT and AST
• Decreased level of SOD, CAT and GSH
• Increased level of NO
Bone• Increased risk of osteoporosis
• Increased apoptosis
• Delayed healing
• Increased activity of ALP
• Increased fracture
Kidney• Increased level of urea and creeatinine
• Increased level of cytokines
• Dilation and destruction of epithelial cells
• Increased level of MDA
Lung• Increased incidence of lung cancer
• Emphysema and increased interstitial tissue
• Increased level of MDA
• Decreased level of GSH
Nervous system• Increased activity of amygdala
• Induction of action potential
• Increased level of inflammasome
• Decreased level of ER-b
Male reproductive system• Decreased level of testosterone
• Decreased level of LH and FSH
• Abnormal sperm
• Decreased gametogenesis
Female reproductive system• Decreased level of ovarian reserve
• Lower uterine receptivity
• Disruption of endometrial decidualization
• Degeneration of endometrium
Cardiovscular system• Endothelial dysfunction
• Risk factor for CVD
• Increased blood pressure
• Decresed coronary blood flow

Table1: Major adverse effects of nicotine on various organs and systems.

Until now, we explained the adverse effects of nicotine on the different organs and systems of body, but the route that nicotine uses to exert its effects, is interesting. Oxidative Stress The most important pathway that nicotine uses is oxidative stress. The proteins of cells, membrane lipids and nucleic acids are affected by high levels of free radicals [216]. Reactive oxygen species include different chemical materials such as superoxide anions, hydroxyl radicals and hydrogen peroxide. They are different in term of stability, so that superoxide or hydroxy radicals are instable, whereas hydrogen peroxide has long life with high diffusible ability. The endogenous (intracellular) and exogenous manners are the sources that can produce free radicals [217, 218]. Endogenous sources include mitochondria, peroxisomes lipoxygenases, NADPH oxidase and cytochrome P450. Exogenous sources include ultraviolet light, ionizing radiation, chemotherapeutics, inflammatory cytokines and environmental toxins [219]. Oxidative stress is the imbalance between the production of free radicals and ability of antioxidant defense members [220]. As we showed, nicotine not only enhances production of ROS, but also depletes the antioxidant reserves. One of the enzymes that has an important role in neutralizing the adverse effects of ROS and nicotine, is glutathione peroxidase (GPX). To describe the role of GPX, first of all, we explain the role of glutathione (GSH). GSH owns sulfhydryl groups and has low level in mammalian tissues. GSH is vital for neutralizing free radicals. There are two forms of glutathione: reduced (GSH) and oxidized (GSSG) forms. The reduced form has electron in thiol groups of cysteine residues which gives it to the ROS to inhibit their instability. The GPX incorporates this molecule with another glutathione and produces glutathione disulfide

Figure 2: The functions of GSH and GR are impaired by nicotine.
Click to enlarge
Figure 2: The functions of GSH and GR are impaired by nicotine.

Throwing away the hydrogen peroxide from erythrocytes is performed by catalase (CAT) that shows its remarkable role. Also, CAT is one of the main enzymes of all peroxisomes. It has been shown that the levels of CAT and superoxide dismutase (SOD) decreased at the result of exposing to nicotine. The lipid bilayer that regulates the permeability of cells, is formed by polar lipids (structural components). Glycerol-based lipid is the most important component forming this bilayer. The polarity and permeability are controlled by lipids that suggests the significant role of lipids in regulating the normal condition of a membrane organelle [222]. Lipid peroxidation is one of the results of stress oxidative that is produced by nicotine toxicity. It has been shown that numerous and excessive concentrations of ROS produce damages in lipids [223]. One of the metabolites of lipid peroxidation is 4-hydroxyl-2-nonenals (4-NHE) that is so energetic. 4-NHE can regulate some signaling pathways. It has been reported that mitochondria generate 4-NHE and high level of ROS. Also, it has been shown that 4-NHE- derived metabolites in mitochondria participate in the beginning and advancement of cancer [130, 224, 225, 226, 227, 228], so suggests the possible role of nicotine toxicity in producing cancer.

Conclusion

The smoking habit is increasing and what are obvious are the adverse effects of nicotine. Nicotine negatively affects all the organs and systems of body such as liver, kidney, nervous and reproductive and cardiovascular systems, lung and bone that we discussed these effects with details. Also, nicotine increases the synthesis of ROS and also evacuates the antioxidant defense system. Due to the lack of a comprehensive review of effects of nicotine, this review provides a platform for further research of adverse effects of nicotine exposure. Conflict of interest: Author declares that there is no conflict of interests in the course of conducting this research.

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@article{zahra2019,
  title   = {A Mechanistic Review of Nicotine Toxicity with Recent Updates},
  author  = {Zahra A},
  journal = {International Journal of Biochemistry & Physiology},
  year    = {2019},
  volume  = {4},
  number  = {2},
  doi     = {10.23880/ijbp-16000155}
}
Zahra A (2019). A Mechanistic Review of Nicotine Toxicity with Recent Updates. International Journal of Biochemistry & Physiology, 4(2). https://doi.org/10.23880/ijbp-16000155
TY  - JOUR
TI  - A Mechanistic Review of Nicotine Toxicity with Recent Updates
AU  - Zahra A
JO  - International Journal of Biochemistry & Physiology
PY  - 2019
VL  - 4
IS  - 2
DO  - 10.23880/ijbp-16000155
ER  -