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Toxicology
Smoking is recognized as a significant risk factor for numerous disorders, including cardiovascular diseases, respiratory conditions, and various forms of cancer. While the exact pathogenic mechanisms continue to be explored, the induction of oxidative stress via the production of excess reactive oxygen species (ROS) is widely accepted as a primary molecular event that predisposes individuals to these smoking-related ailments. Oxidative stress represents a physiological condition characterized by an imbalance between oxidative and antioxidative potentials.
- smoking
- cigarette smoke
- reactive oxygen species
- oxidative stress
- biomarkers
- antioxidant system
1. Introduction
Smoking is widely recognized as a significant risk factor for numerous diseases, including cardiovascular conditions, respiratory illnesses, and various types of cancers [1]. The toxicological implications of smoking are attributed to a number of mechanisms, many of which involve intricate molecular events. Thus, despite our increasing understanding, the molecular mechanisms continue to be a focus of rigorous investigation. Oxidative stress is widely identified as one of the key molecular events mediating the pathogenesis of smoking-associated diseases [2,3].
Oxidative stress represents a physiological condition characterized by an imbalance between oxidative and antioxidative potentials [4]. Such imbalance typically involves an excessive or deregulated production of prooxidants and/or a dysfunction within the antioxidant system. Prooxidants, which incite oxidative stress, comprise reactive oxygen species (ROS), radicals, and other oxidizing agents. In contrast, the antioxidant system involves both enzymatic antioxidants like superoxide dismutase (SOD), catalase, and glutathione (GSH) peroxidase, and non-enzymatic antioxidants such as GSH, carotenoids, and vitamins C and E [5].
Prooxidants, typified by ROS and radicals, represent highly reactive molecules that function as oxidizing agents in redox reactions. ROS, the primary endogenous prooxidants, are derivatives of molecular oxygen (O2) exhibiting greater reactivity compared to O2 itself [6]. These include species such as superoxide (O2•−), hydrogen peroxide (H2O2), hypochlorous acid (HOCl), and peroxynitrite/peroxynitrous acid (ONOO−/ONOOH). These are produced endogenously through sources like the mitochondrial electron transport chain (ETC) and enzymes including NADPH oxidase (NOX), xanthine oxidase, nitric oxide synthase (NOS), and cytochromes P450 [7,8,9,10,11]. Moreover, they are generated via chemical reactions that involve transition metals like Fe and Cu [12]. Exogenous factors, including air pollutants and radiation, can also induce or stimulate their production [12]. The genesis of oxidative stress is not solely due to excessive or unregulated ROS formation but also linked to the dysregulation of the antioxidant system. Decreased antioxidant capacity can exacerbate ROS production and make biomolecules more susceptible to damage from prooxidants [13]. It is pertinent to mention that ROS, traditionally deemed hazardous byproducts of physiological processes or xenobiotics, also serve as signaling molecules, regulating various redox signaling involved in physiological processes [14]. ROS play crucial roles in diverse cellular events, such as growth, proliferation, differentiation, and apoptosis, by modulating redox-sensitive signaling molecules [14]. Furthermore, excessive ROS can inflict direct and nonspecific damage to various biomolecules, including lipids, proteins, and nucleic acids [13].
2. ROS Formation or Oxidative Stress in Smokers
Elevated oxidative stress, manifested by an intensified production of ROS, is a hallmark characteristic of smokers [4,8,22,23]. Such an observation is primarily grounded in clinical studies showcasing altered profiles of oxidative stress biomarkers in individuals who smoke. The majority of these biomarkers originate from the oxidative modification of biomolecules, encompassing lipid peroxidation products like 4-hydroxynonenal (4-HNE) [24], malondialdehyde (MDA) [25], and 8-isoprostane [26]; protein byproducts altered through oxidation such as protein carbonyls, 3-nitrotyrosine [27], and oxidized α-1 antitrypsin [28,29]; oxidized nucleic acid metabolites, such as 8-hydroxy-2′-deoxyguanosine (8-OHdG) [30]; and the antioxidant levels, notably GSH [31,32]. These biomarkers have been identified and quantified in an array of biological specimens including urine, blood, epithelial lining fluid, sputum, and saliva.
These oxidative stress biomarkers exhibit a tendency toward elevated levels within the respiratory system, the primary site of exposure to cigarette smoke [33,34,35]. For instance, 8-OHdG levels in the lung were discovered to be significantly higher in smokers than nonsmokers, with the degree of this elevation proportional to the cigarette smoking volume [33]. MDA levels were found to be increased in lung tissue samples from patients diagnosed with lung cancer [36]. Additionally, amplified levels of 8-isoprostane and 3-nitrotyrosine were observed in saliva and bronchial mucosa, respectively, from both asymptomatic smokers and patients diagnosed with chronic obstructive pulmonary disease (COPD), a common smoking-related condition [37,38].
Apart from the primary exposure site, biomarkers in blood and urine have also been examined to evaluate systemic oxidative stress [39]. Notably, the levels of MDA [39], 8-isoprostane [40,41], 3-nitrotyrosine [42], carbonyl content [43], and oxidized α-1 antitrypsin [28,29] in blood plasma or serum were higher in smokers compared to nonsmokers. Correspondingly, elevated urinary levels of 8-isoprostane [42], MDA [44], and 8-OHdG [45,46] were reported in smokers, demonstrating a quantitative correlation between the number of cigarettes consumed daily and the increment of these biomarkers [46]. It is crucial to note that the biomarker levels in blood or urine are influenced by both excretion and formation. Chronic smoking is known to impair renal function, which could potentially elevate these biomarker levels due to reduced excretion, in addition to the increased formation [30]. Therefore, kidney function must be factored into the interpretation of these findings. For example, the 8-isoprostane/creatinine ratio presents an effective index for oxidative stress assessment [42]. Moreover, high levels of 4-HNE and 8-OHdG have been identified in placenta samples from smoking mothers [47], indicating an association between maternal smoking and intrauterine oxidative stress. Smoking induces oxidative stress not only locally within the respiratory system but also at a systemic level.
Studies have substantiated the detrimental impact of smoking on the antioxidant system, precipitating a reduction in Trolox equivalent antioxidant capacity in plasma, an index of antioxidant capacity [48,49]. The literature abounds with evidence illustrating the adverse effects of smoking on antioxidants including, but not limited to, vitamins A, C, and E, carotene, and soluble thiol pools such as GSH [50,51]. A majority of these investigations have reported a decrease in these antioxidants consequent to smoking. However, a subset of studies has documented negligible alterations or even augmentation in GSH levels, potentially attributable to a compensatory mechanism countering depletion or a rebound phenomenon [52,53]. Although complicate molecular mechanisms are implicated, Nrf2 appears to play crucial roles in this compensation by upregulating enzymes responsible for GSH biosynthesis and regeneration [54]. Additionally, smoking has been found to suppress or downregulate enzymatic antioxidant systems including SOD and catalase in erythrocytes and plasma [55,56], as well as extracellular SOD in serum [57].
Given that the bulk of these studies have focused on chronic smokers, the perturbations in these biomarkers may represent the fallout of extended exposure to CS, suggesting that CS-induced oxidative stress could be a sequel to prolonged incidents such as smoking-induced inflammation or metabolic disorders. Nonetheless, even transient exposure to CS has been sufficient to amplify biomarkers of oxidative stress. As an example, the consumption of a single cigarette led to an upsurge in 8-isoprostane and soluble NOX2-derived peptide, a marker for NOX2 activation, along with a decrease in NO bioavailability and vitamin E in serum within 30 min [58,59]. Correspondingly, 8-OHdG levels in peripheral leukocytes were noted to rise a mere 10 min after smoking two cigarettes [60]. Passive smoking too has been found to increase plasma 8-isoprostane levels in nonsmokers within 30 min [61]. The rapid escalation in these biomarkers suggests an immediate induction of ROS formation by CS, irrespective of the presence of pathological conditions [62]. This notion is bolstered by findings that demonstrate the restoration of biomarker levels following smoking cessation, even in the absence of symptom improvement in patients with diabetes, hypercholesterolemia, or hypertension [63].
Regrettably, few studies have successfully detected a direct increase in ROS in reasonable ways rather than simply observing oxidative stress markers in human subjects, presumably due to the inherent technical challenges associated with measuring ROS. A pioneering study detected chemiluminescence in the blood plasma of smokers, which promptly ceased following smoking cessation, leading researchers to postulate its origin in ROS such as singlet oxygen derived from CS [64]. Another investigation, which analyzed expired breath condensate, reported elevated levels of hydrogen peroxide in smokers compared to nonsmokers, indicative of CS-induced hydrogen peroxide formation in the airway epithelial lining fluid [65]. This collective body of evidence intimates a direct elevation of ROS as a result of smoking.
This entry is adapted from the peer-reviewed paper 10.3390/antiox12091732
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