The importance of polymorphisms in the genes encoding glutathione S-transferase isoenzymes in development of selected cancers and cardiovascular diseases.

Glutathione S-transferases are a family of enzymes, whose main role is to detoxify cells from many exogenous factors, such as xenobiotics or carcinogens. It has also been proven that changes in the genes encoding these enzymes may affect the incidence of selected cancers and cardiovascular diseases. The aim of this study was to review the most important reports related to the role of glutathione S-transferases in the pathophysiology of two of the most common diseases in modern society - cancers and cardiovascular diseases. It was shown that polymorphisms in the genes encoding glutathione S-transferases are associated with the development of these diseases. However, depending on the ethnic group, the researchers obtained divergent results related to this field. In the case of the GSTP1 A/G gene polymorphism was shown an increased incidence of breast cancer in Asian women, while this relationship in European and African women was not found. Similarly. In the case of cardiovascular diseases, the differences in the influence of GSTM1, GSTT1, GSTP1 and GSTA1 polymorphisms on their development or lack of it depending on the continent were shown. These examples show that the development of the above-mentioned diseases is not only influenced by genetic changes, but their pathophysiology is more complex. The mere presence of a specific genotype within a studied polymorphism may not predispose to cancer, but in combination with environmental factors, which often depend on the place of residence, it may elevate the chance of developing the selected disease.

Importance of Genetic Polymorphisms in MT1 and MT2 Genes in Metals Homeostasis and Their Relationship with the Risk of Acute Pancreatitis Occurrence in Smokers-Preliminary Findings.

This study was aimed at evaluating the changes in metallothionein (MT) concentration in the blood of patients with acute pancreatitis (AP) and healthy subjects, taking into account the extracellular (plasma) and intracellular (erythrocyte lysate) compartments. The impact of single-nucleotide polymorphisms (SNPs) in the MT1A (rs11640851), MT1B (rs964372) and MT2A (rs10636) genes on MT concentration and their association with the concentration of metals (Cu, Zn, Cd) and ceruloplasmin as Cu-related proteins were analyzed. The concentration of a high-sensitivity C-reactive protein (hs-CRP) and IL-6 as markers of inflammation, and malonyldialdehyde (MDA), superoxide dismutase (SODs) activity and the value of total antioxidant capacity (TAC) as parameters describing the pro/antioxidative balance were also assessed. In the AP patient groups, an increased MT concentration in erythrocyte lysate compared to healthy subjects was shown, especially in individuals with the GG genotype for rs964372 in the MT1B gene. A Zn concentration was especially decreased in the blood of smoking AP patients with the AA genotype for SNP rs11640851 in the MT1A gene and the GC genotype for SNP rs10636 in MT2A, compared to non-smokers with AP, which was accompanied by an increase in the value of the Cu/Zn ratio. The exposure to tobacco smoke xenobiotics increased the risk of AP occurrence in subjects with the CC genotype for SNP rs11640851 in the MT1A gene by more than fourfold. The investigated polymorphisms, rs11640851 in the MT1A gene, rs964372 in the MT1B gene and rs10636 in the MT2A gene, seem to be an important factor in maintaining homeostasis in an organism under oxidative stress conditions.

Increased risk of acute pancreatitis occurrence in smokers with rs5751901 polymorphisms in GGT1 gene.

Objectives: The study was aimed to assess γ­glutamyltransferase (GGT) activity and concentration as a marker of oxidative stress induced by exposure to tobacco smoke in acute pancreatitis (AP) course. Examination of the relationship between GGT activity/concentration and single-nucleotide polymorphism (SNP rs5751901 and rs2236626) in GGT1 gene was performed. Subjects and methods: We examined SNPs in 38 AP patients and 51 healthy subjects by PCR-RFLP methods. GGT concentration in blood was measured with the use of the ELISA method; GGT activity and GSH concentration were measured by the Szasz and Patterson methods, respectively. Results: In the non-AP smokers group with TC genotype for SNPrs5751901 an increased blood GGT activity compared to smokers with CC genotypes was shown. In the course of AP was observed an elevated GGT activity and the value of GGT activity/GGT concentration ratio in smokers compared to non-smokers, in AP patients with TC genotypes and CC genotypes, respectively, for both SNP: rs5751901 and rs2236626. In the group of smoking AP patients with the CC and TC genotypes in rs5751901 locus and CC and TT genotypes in rs2236626 locus a decreases in GSH concentration during hospitalization were noted. Conclusions: SNP rs5751901 and rs2236626 cause changes in GGT activity. Smoking in the AP course contributes to increased GGT activity and excessive GSH use up in patients with TC and CC genotypes for both SNPs. Exposure to smoke xenobiotics enhances (3-fold) the risk of AP occurrence in individuals with TC genotypes for SNP rs5751901.

Decreases in Paraoxonase-1 Activities Promote a Pro-inflammatory Effect of Lipids Peroxidation Products in Non-smoking and Smoking Patients with Acute Pancreatitis.

Aim: The study investigated the extent to which tobacco smoke exposure causes changes in lipids biochemistry through measurement blood concentrations of: paraoxonase-1 (PON-1) activities as lipid-bound enzyme into cell membrane, concentration of malonyldialdehyde (MDA), protein adducts of 4-hydroxynonenal (HNE-adducts), oxidized low density lipoproteins (oxLDL), total cholesterol (CH) and high-density lipoprotein cholesterol (HDL). Additionally, the activity of P isoform of glutathione S-transferase (GST-π) was measured. Methods: Investigations were performed in the blood of patients with acute pancreatitis (AP) on the 1st, 3rd and 7th day of hospitalization and in healthy volunteers. The activities of PON-1 forms, GST-π were determined spectrophotometrically. Concentrations of PON-1, MDA, HNE-adducts, oxLDL, HDL, CH were measured using commercial tests. Results: Near 2-fold higher concentrations of MDA, HNE-adducts, oxLDL, correlating with inflammatory markers in AP patients compared to healthy subjects were demonstrated, which were accompanied by gradually increasing CH/HDL ratio during hospitalization. During hospital treatment, decreased activities of all PON-1 subtypes were observed in AP patients compared to healthy subjects, more pronounced in tobacco smokers. A decreased PON-1 phosphotriesterase activity in non-AP control group smokers compared to non-smokers was noted. In non-smoking AP patients GST-π activity normalized during hospitalization in contrast to smokers. Conclusions: GST-π and PON-1 phosphotriesterase activities seem to be a sensitive marker of pro/antioxidative imbalance in smokers. Lipids peroxidation products generated during AP can intensify preexisting inflammation. Increasing stay in the hospital was associated with worsening of lipids peroxidation markers and the parameters of lipid profile, in both non-smoking and smoking AP patients, what can indicate that the oxidative-inflammatory process are not extinguished.

Influence of oral contraceptives on lipid profile and paraoxonase and commonly hepatic enzymes activities.

BACKGROUND: The aim of the study was to verify the influence of oral contraceptives (OCs) on lipid profile and the arylesterase, lactonase and phosphotriesterase activities of paraoxonase 1 (PON1). Also commonly hepatic enzymes: aspartate aminotransferase (AST), alanine aminotransferase (ALT) and γ-glutamyltranspherase (GGT) were measured. METHODS: Lipid profile and hepatic enzymes were determined using commercial available reagents. Paraoxonase activities were estimated using earlier published procedures. Blood samples were collected from 120 women of similar age (22.6±1.0 years) with similar BMI (20.71±2.20 kg/m2 ). Participations were divided into two groups: 74 females do not take (group A) and 46 women taking OCs (group B). RESULTS: Higher triglycerides and lower low-density lipoproteins levels were observed in group B than in group A) (56.9±19.7 mg/dL. Castelli risk index I was significantly higher in group B when compared to group A (P<.0001), whereas we did not observe any statistically significant differences in Castelli risk index II value between studied groups. In group B, increase in ALT, AST and GGT activities were found, while the de Ritis ratio was lower in group B than in group A. In group B, lower phosphotriesterase activity and higher arylesterase and lactonase activities were found when compared to group A. CONCLUSION: Higher ALT, AST and GGT activities in serum as well as changes in lipid profile and PON activities can indicate that OCs usage can cause disorder in these parameters in the serum of women taking OCs.

Resistin as a Prooxidant Factor and Predictor of Endothelium Damage in Patients with Mild Acute Pancreatitis Exposed to Tobacco Smoke Xenobiotics.

OBJECTIVES: The study was aimed to assess the influence of tobacco smoke exposure on the intensity of inflammation measured by IL-6, α1-antitripsin (AAT) and α1-acid glycoprotein (AGP) concentrations, and Cd level and oxidative stress intensity measured by advanced oxidation protein product (AOPP) concentration in the blood of healthy subjects and AP patients during hospitalization. Endothelin-1 (ET-1) and resistin concentrations, markers of endothelium injury, were determined. RESULTS: An increased IL-6 concentration in healthy smokers compared to nonsmokers and AP patients compared to controls was shown. An increased AAT and AGP concentrations during hospitalization of AP patients were noted, in both smokers (AAT, AGP) and nonsmokers (AAT). In comparison to control groups, in AP patients, a 2-fold increased resistin concentration correlating with ET-1 concentration and decreased albumin concentration accompanied by increased AOPP concentration were demonstrated. AOPP concentration was higher in smokers with AP compared to nonsmokers and gradually enhanced during their hospitalization. CONCLUSIONS: Tobacco smoke exposure can have a proinflammatory effect in both healthy subjects and AP patients. Increased resistin concentration in AP patients negatively correlating with albumin concentration has prooxidative effect on this protein resulting in enhanced AOPP level. Increased resistin concentration can intensify AAT and AGP production during AP.

CC16 as an early marker of harmful effect of tobacco smoke exposure in women.

Tobacco smoke xenobiotics can damage lung epithelium causing the impairment of its functions and Clara cell destruction. It was shown that Clara cell secretory protein (CC16) can be recognized as a useful marker of toxic effect of tobacco smoke on lung epithelium and CC16 concentration in the blood was positively correlated with the continuity of blood-air barrier. The aim of our study was to examine whether tobacco smoke can cause changes in the concentration of cotinine and CC16 in initial smokers. The study was also aimed to assess weather serum CC16 concentration can be an early marker of tobacco smoke exposure. Material and Methods: The investigations were performed in the blood of 105 volunteers in 21-28 years old. The study population was divided into smokers and non-smokers on the base of personal interview and determination of cotinine concentration in serum (ELISA method). The concentration of Clara cells secretory protein (CC16) using commercial test (ELISA method) was measured. Results: It was shown a significant increase in cotinine concentration in smokers compared to nonsmokers in both women and men. An increase in CC16 concentration in the group of smoking women compared to non-smoking women was noted. The level of this protein in the blood of men was 33.67 ± 10.03 ng/ml and 32.96 ± 12.11 ng/ml in non-smokers and smokers, respectively. The analyze of CC16 concentration depending on the intensity of smoking was shown a significant influence of tobacco smoke exposure on CC16 level in the blood of women. Conclusions: The observed changes in CC16 concentrations in terms of intensity of cigarette smoking can indicate a greater sensitivity female than men organism on tobacco smoke exposure. CC16 can be considered as a useful marker of tobacco smoke exposure in women.

Mechanisms of interaction of the N-acetyl-p-aminophenol metabolites in terms of nephrotoxicity.

CONTEXT: Epidemiological studies have demonstrated that chronic use of N-acetyl-p-aminophenol is correlated with the occurrence of renal dysfunction. OBJECTIVE: Aim of this study was to review the literature on the mechanisms of interaction N-acetyl-p-aminophenol metabolites in terms of nephrotoxicity. METHODS: We present a literature review of studies published in English language on the damage effects of N-acetyl-p-aminophenol on the kidneys, accessed through PubMed database. RESULTS: The pathogenesis of drug-induced nephrotoxicity attributed to the action of cytochrome P450 enzymes, prostaglandin endoperoxide synthase (PGES) and N-deacetylase. The metabolism of N-acetyl-p-aminophenol with the participation of PGES more explicit is in the core of kidney, whereas cytochrome P450 enzymes play role in the renal cortex. Due to the action of cytochrome P450 and N-deacetylase, a very reactive N-acetyl-p-benzochinoimine (NAPQI) is formed. The result of the catalytic activity of PGES is p-benzoquinone (PBQI) production. The formation of NAPQI and PBQI is accompanied by the production of free radicals. Metabolites can connect covalently with sulfhydryl groups of renal proteins, what can cause the injury of proximal tubules. N-acetyl-p-aminophenol may initiate the apoptosis process involving activation of caspase-9 and caspase-3, but also caspase-12 as a result of generation of free radicals. CONCLUSIONS: The process of NAPQI and PBQI formation can increase oxidative stress that promotes the kidneys damage. The ability of metabolites to produce covalent bonds with sulfhydryl groups of proteins can increase the nephrotoxicity. It was assumed that the induction of apoptosis in renal tubular epithelial cells, and not necrosis underlies the nephrotoxic potential of N-acetyl-p-aminophenol.

The antioxidant profiles, lysosomal and membrane enzymes activity in patients with acute pancreatitis.

Oxidative stress and inflammatory mediators, such as IL-6, play an important role in the pathophysiology of acute pancreatitis. The study was aimed to assess the degree of the pro/antioxidative imbalance and estimate which antioxidant plays a role in the maintenance of pro/antioxidative balance during acute pancreatitis. The study was investigated in the blood of 32 patients with acute pancreatitis and 37 healthy subjects. IL-6 concentration as early marker of inflammation was determinated. The intensity of oxidative stress was assessed by TBARS concentration. To investigate antioxidative status, the GPx and Cu/Zn SOD activities and the levels of GSH, MT, SH groups, and TRAP were measured. The concentrations of Cu and Zn as ions participating in the maintenance of antioxidant enzymes stability and playing a role in the course of disease were determinated. The activities of GGT, AAP, NAG, and ß-GD as markers of tissue damage were also measured. An increase in IL-6 concentration, which correlated with Ranson criteria, and an increase in GPx activity, levels of MT, TBARS, or GGT, and NAG activities in patients group compared to healthy subjects were demonstrated. A decrease in GSH level in patients group compared to control group was noted. The studies suggest that GPx/GSH and MT play the role of the first line of defence against oxidative stress and pro/antioxidant imbalance in the course of acute pancreatitis.

Modulatory Effect of Lifestyle-Related, Environmental and Genetic Factors on Paraoxonase-1 Activity: A Review.

Paraoxonase-1 (PON1) is a calcium-dependent, HDL-bound serum hydrolase active toward a wide variety of substrates. PON1 displays three types of activities, among which lactonase, paraoxonase, arylesterase and phosphotriesterase can be distinguished. Not only is this enzyme a major organophosphate compound detoxifier, but it is also an important constituent of the cellular antioxidant system and has anti-inflammatory and antiatherogenic functions. The concentration and activity of PON1 is highly variable among individuals, and these differences can be both of genetic origin and be a subject of epigenetic regulation. Owing to the fact that, in recent decades, the exposure of humans to an increasing number of different xenobiotics has been continuously rising, the issues concerning the role and activity of PON1 shall be reconsidered with particular attention to growing pharmaceuticals intake, dietary habits and environmental awareness. In the following manuscript, the current state of knowledge concerning the influence of certain modifiable and unmodifiable factors, including smoking, alcohol intake, gender, age and genotype variation on PON1 activity, along with pathways through which these could interfere with the enzyme's protective functions, is presented and discussed. Since exposure to certain xenobiotics plays a key role in PON1 activity, the influence of organophosphates, heavy metals and several pharmaceutical agents is also specified.

Association of genetic variants in the GPX1 and GPX4 genes with the activities of glutathione-dependent enzymes, their interaction with smoking and the risk of acute pancreatitis.

Genetic factors and tobacco smoke exposure can be associated with an increased risk of acute pancreatitis (AP). The pathogenesis of AP is associated with intensive oxidative stress. Glutathione peroxidase (GPx) is one of many enzymes involved in the neutralization of free radicals. This study aimed to investigate the impact of SNP rs1050450 in the GPX1 gene and rs713041 in the GPX4 gene on the activity of total GPx in a group of AP patients and healthy subjects. It was found that AP can contribute to decreased GPx activity (in plasma and erythrocyte lysate) accompanied by an increased glutathione reductase (GR) activity and decreased glutathione (GSH) concentration in two groups, non-smokers and smokers. A decreased GPx activity in erythrocyte lysate of AP patients compared to healthy subjects was associated with the occurrence of the CC genotype for SNP rs1050450. It was noted an increased GPx activity and decreased GR activity in erythrocytes of non-smoking AP patients with the TT genotype compared to subjects with the CC and TC genotype for SNP rs713041. However, in the group of smoking AP patients with this genotype, GR activity was elevated compared to non-smokers, which was accompanied by increased GSH concentration. These results can indicate that smoking in the course of AP can change the involvement of antioxidants in dependence on the genotype for the examined SNPs. The CC genotype for SNP rs1050450 and the TT genotype for rs713041 increases the risk of AP recurrence, which may be associated with increased MDA concentration.

Importance of Polymorphisms in the Gene of Paraoxonase-1 (SNP rs662) and Apolipoprotein A-I (SNP rs670 and rs5069) in Non-Smoking and Smoking Healthy Subjects and Patients with Acute Pancreatitis.

Oxidative stress has been implicated in the initiation of acute pancreatitis (AP). HDL is considered to be a preventing factor against cell membrane oxidation, thanks to the presence on its surface of apolipoprotein A-I (apoA-I) and paraoxonase-1 (PON1), which activity can be modified by genetic and environmental factors. The impact of SNP rs662 in the PON1 gene and SNP rs670 and rs5069 in the APOAI gene on PON1 activities and its concentration in the population of AP patients and healthy volunteers was investigated. In the group of patients with AP, a decreased HDL concentration and PON1 activities were observed. A decrease in the aryloesterase and lactonase activities of PON1 in AP patients with the TT genotype for SNP rs662 (especially in smokers) was found. In the group of patients with the AA genotype (rs670), the highest concentrations of HDL and apoA-I were observed, which were gradually decreasing in the course of AP. Changes in the concentration of apoA-I were associated with the changes in the concentration and activities of PON1 in the AP patients with the AA genotype for SNP rs670. A decreasing apoA-I concentration contributing to lowering PON1 concentration and its activities during the hospitalization of AP patients with the CC genotype for SNP rs5069 were shown. Therefore, more susceptibility of persons with the CC genotype for SNP rs5069 to pro/antioxidative imbalance was shown. In this process, an important role was played by the HDL level and its interaction with PON1 and apoA-I.

Structural changes in selected human proteins induced by exposure to quantum dots, their biological relevance and possible biomedical applications.

Quantum dots (QDs) are semi-conductor luminescent nanocrystals usually of 2-10 nm diameter, attracting the significant attention in biomedical studies since emerged. Due to their unique optical and electronic properties, i.e. wide absorption spectra, narrow tunable emission bands or stable, bright photoluminescence, QDs seem to be ideally suited for multi-colour, simultaneous bioimaging and cellular labeling at the molecular level as new-generation probes. A highly reactive surface of QDs allows for conjugating them to biomolecules, what enables their direct binding to areas of interest inside or outside the cell for biosensing or targeted delivery. Particularly protein-QDs conjugates are current subjects of research, as features of QDs can be combined with protein specific functionalities and therefore used as a complex in variety of biomedical applications. It is known that QDs are able to interact with cells, organelles and macromolecules of the human body after administration. QDs are reported to cause changes at proteins level, including unfolding and three-dimensional structure alterations which might hamper proteins from performing their physiological functions and thereby limit the use of QD-protein conjugates in vivo. Moreover, these changes may trigger unwanted cellular outcomes as the effect of different signaling pathways activation. In this review, characteristics of QDs interactions with certain human proteins are presented and discussed. Besides that, the following manuscript provides an overview on structural changes of specific proteins exposed to QDs and their biological and biomedical relevance.

Association of Genetic Variants in IL6 Gene (rs1800795) with the Concentration of Inflammatory Markers (IL-6, hs-CRP) and Superoxide Dismutase in the Blood of Patients with Acute Pancreatitis-Preliminary Findings.

In the course of acute pancreatitis, interleukin-6 plays an important role as a mediator in the inflammatory response. The course of inflammatory disease is associated with intensive oxidative stress, which may activate transcription factors leading to gene-expression changes. Isoenzymes of superoxide dismutase are involved in the defense against free radicals. This study aimed to evaluate changes in IL-6 concentration and the concentration/activity of superoxide dismutase isoenzymes (SOD1, SOD2, and SOD3) in the blood of patients with acute pancreatitis (AP) in terms of rs1800795 polymorphism in the IL6 gene. In the smoking AP patients group with the GC and GG genotypes, the plasma SOD1 concentration was significantly higher (p = 0.0146 and p = 0.0250, respectively) than in patients with CC genotype for SNP rs1800795 in the IL6 gene. An increase in SOD1 concentration in erythrocytes of AP patients with GC genotypes was also demonstrated compared to the individuals from the group with GG genotype (p = 0.0408). Furthermore, a positive correlation between IL-6 and SOD1 concentrations in the plasma of AP patients with GC genotype for SNP rs1800795 was shown. These results indicate that SOD1 may play a protective role against oxidative damage induced by inflammation in the group of AP patients with GC genotype.

Activity of glutathione S-transferase and its π isoenzyme in the context of single nucleotide polymorphism in the GSTP1 gene (rs1695) and tobacco smoke exposure in the patients with acute pancreatitis and healthy subjects.

Oxidative stress associated with the course of acute pancreatitis (AP) can cause changes in the involvement of antioxidants, which can result in the increased production of free radicals with pro-inflammatory potential. Through its noncatalytic activity, the glutathione S-transferase and its π isoenzyme (GST-π), apart from cellular xenobiotics detoxification, are involved in the regulation of cellular signalling, metabolism and apoptosis. This study aimed to evaluate the impact of SNP rs1695 in the GSTP1 gene on GST and GST-π activity in healthy subjects and patients with acute pancreatitis (AP). The concentration of glutathione (GSH) as an important component of the antioxidant system, necessary for environmental xenobiotics detoxification by GST, and malonyldialdehyde (MDA) as a marker of oxidative stress induced by inflammation were also assessed. SNP was examined in 39 AP patients and 51 healthy subjects using PCR-RFLP methods. GST activity (in plasma and erythrocyte lysate) and GST-π activity (in erythrocyte lysate) were measured using the spectrophotometric method with 1-chloro-2,4-dinitrobenzene and ethacrynic acid as substrate, respectively. Blood GSH concentration was measured using the Patterson method. Concentrations of high-sensitive C-reactive protein (hs-CRP) and MDA were measured using commercial tests. In the blood of non-smoking AP patients with GG genotypes for SNP rs1695 in the GSTP1 gene, the lowest GST-π activity was shown. It was accompanied by the lowest hsCRP concentration in this group. In the blood of smoking healthy subjects with AG genotype, a decrease in GST-π activity was noted compared to non-smokers from this group. However, in the blood of smokers with AP, a gradually decreasing GST-π activity was noted in individuals with AA genotype, which was associated with the increasing MDA concentration. It confirms the role of GST-π in the neutralization of oxidative stress induced by the exposure to smoke xenobiotics.

The Changes in Stress Coping, Alcohol Use, Cigarette Smoking and Physical Activity during COVID-19 Related Lockdown in Medical Students in Poland.

The ongoing COVID-19 pandemic has significantly limited social contacts, thus contributing to deepening isolation. Therefore, SARS-CoV-2 exerted on humanity not only a physical impact but also a psychological one, often increasing the feeling of stress. The long-term effects of such a state could include the management of depression, so our study aimed to analyze groups of medical students in different periods of the pandemic (at the beginning of the pandemic, after half a year of the pandemic, after one year of the pandemic) in order to assess the impact of this situation on coping with stress. The impact of the pandemic on the development of stress factors such as alcohol consumption and smoking was also studied. The level of physical activity in the context of coping with an uncertain situation was also assessed. The impact of the above-mentioned factors on the behavior of students, including the Mini-COPE questionnaire, AUDIT test, the Fagerström test and the IPAQ questionnaire was analyzed. It has been shown that as the pandemic and the lockdown progressed, patients consumed more often or larger amounts of alcohol, smoked more cigarettes, and levels of physical activity decreased. All these factors may have had some impact on the deterioration of coping with stress among the respondents, which would indicate that the COVID-19 pandemic significantly contributed to an increase in the sense of stress among the students.

Changes in the Activity and Concentration of Superoxide Dismutase Isoenzymes (Cu/Zn SOD, MnSOD) in the Blood of Healthy Subjects and Patients with Acute Pancreatitis.

This study was aimed at evaluating the changes in the concentration and activity of all superoxide dismutase isoenzymes (SOD1, SOD2, SOD3) in the blood of patients with acute pancreatitis (AP) and healthy subjects, taking into account the extracellular (plasma) and intracellular (erythrocyte lysate) compartment. The relationships between the activity/concentration of SODs, metal concentration and the markers of inflammation were evaluated. To assess the pro/antioxidative imbalance, the malonyldialdehyde (MDA) concentration and the value of total antioxidant capacity (TAC) were measured. The impact of single-nucleotide polymorphism (SNP) in the SOD1 gene (rs2070424) on the activity/concentration of SOD1 as the main isoenzyme of the SOD family was also analyzed in this study. The SOD2 activity in erythrocytes was increased compared to plasma: 10-fold in the AP patient group and 5-fold in healthy subjects. The plasma of AP patients showed an increased SOD1 concentration and decreased SOD2 and SOD3 concentrations compared to healthy subjects. The Cu/Zn SOD (SOD1 + SOD3) concentration in plasma of AP patients was elevated compared to healthy subjects, but changes in plasma Cu/Zn SOD (SOD1 + SOD3) activity in the examined groups were not observed. An influence of SNP rs2070424 in the SOD1 gene on the total activity of SOD in AP patients (with AG genotype), accompanied by an increased IL-6 concentration, was observed. In oxidative stress conditions induced by inflammation, the participation of individual forms of plasma SOD isoenzymes in total antioxidative activity of SOD changed. A significant increase in the intracellular SOD1 concentration in plasma of AP patients proves the important role of this isoenzyme in the neutralization of oxidative stress induced by impaired Cu and Zn homeostasis. The presence of increased concentration of SOD2 in erythrocytes of healthy subjects and AP patients confirms the important function of this isoenzyme in the antioxidative defense.

Molecular mechanisms of the impact of smoke-oxidants.

Tobacco smoke is a source of many xenobiotics and free radicals. Reactive oxygen species can affect the body both directly and indirectly, through the activation of both signalling pathways and transcription factors (NF-κB and AP-1). One of the most important signalling cascades which can affect the oxidants in smoke are mitogen-activated protein kinases (MAPK). The mechanism of MAPK pathways activation by reactive oxygen species depends on the stimulation of specific tyrosine kinases and protein tyrosine phosphatases inactivation. An activated MAP protein can initiate AP-1 signalling and interact with many other transcription factors. The components of tobacco smoke with oxidation-reduction properties can have an effect on NF-κB signalling. Binding of NF-κB and AP-1 with DNA is a complicated process, in which coactivators exhibiting internal histone acetyltransferase activity are involved. The balance between histone deacetylases and acetylases is important for the regulation of inflammatory response in the lungs. Tobacco smoke causes increased acetylase activity and decreased deacetylase activity in epithelial lung cells. The result is an increase in the activation of NF-κB and AP-1. Oxygen free radicals from tobacco smoke can change the redox status of cells, which can in turn induce the activation of transcription factors, chromatin remodelling and intensified genes transcription for inflammatory mediators.

Pro-inflammatory effects of metals in persons and animals exposed to tobacco smoke.

Metals present in tobacco smoke have the ability to cause a pro-oxidant/antioxidant imbalance through the direct generation of free radicals in accordance with the Fenton or Haber-Weiss reaction and redox properties. Metals can also interact with antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase) and small molecular antioxidants (glutathione) through binding to SH groups or by replacement of metals ions in the catalytic center of enzymes. Excessive free radicals production can induce an inflammatory response. The aim of this study was to review the information on the induction of inflammation by metals present in tobacco smoke such as lead (Pb), cadmium (Cd), arsenic (As), aluminum (Al), nickel (Ni) and mercury (Hg). In cellular immune response, it was demonstrated that radicals induced by metals can disrupt the transcription signaling pathway mediated by the mitogen-activated protein kinase (induced by Pb), NLRP3-ASC-caspase 1 (induced by Ni), tyrosine kinase Src (induced by As) and the nuclear factor κB (induced by Pb, Ni, Hg). The result of this is a gene transcription for early inflammatory cytokines, such as Interleukine 1ß, Interleukine 6, and Tumor necrosis factor α). These cytokines can cause leukocytes recruitment and secretions of other pro-inflammatory cytokines and chemokines, which intensifies the inflammatory response. Some metals, such as cadmium (Cd), can activate an inflammatory response through tissue damage induction mediated by free radicals, which also results in leukocytes recruitment and cytokines secretions. Inflammation generated by metals can be reduced by metallothionein, which has the ability to scavenge free radicals and bind toxic metals through the release of Zn and oxidation of SH groups.

The influence of the occupational exposure to heavy metals and tobacco smoke on the selected oxidative stress markers in smelters.

The aim of the study was to verify if there is any association between exposure to Cu, Zn, Cd, Pb, As and the formation of malondialdehyde (MDA), 8-hydroxydeoxyguanosine (8-OHdG), advanced oxidation protein products (AOPP), and whether in this process cigarette smoking plays a role. The investigations were performed in the 352 smelters occupationally exposed to heavy metals and 73 persons of control group. Metals concentration was determined by atomic absorption spectrometry. MDA and AOPP concentrations were determined by spectrophotometric methods. The concentration of 8-OHdG was determined by ELISA method. It was demonstrated an increased Cu concentration in smoking smelters compared to non-smoking control group. It was noted no differences in Zn and Mg concentrations between the examined groups. Pb concentration was more than sixfold higher in the group of smoking smelters and about fivefold higher in the group of non-smoking smelters compared to the control groups (smokers and non-smokers). It was shown that Cd concentration in the blood was nearly fivefold higher in the smoking control group compared to the non-smoking control group and more than threefold higher in the group of smoking smelters compared to non-smoking. It was shown an increased As concentration (more than fourfold) and decreased Ca concentration in both groups of smelters compared to control groups. In groups of smelters (smokers and non-smokers), twofold higher MDA and AOPP concentrations, and AOPP/albumin index compared to control groups (smokers and non-smokers) were shown. Tobacco smoke is the major source of Cd in the blood of smelters. Occupational exposure causes accumulation of Pb in the blood. Occupational exposure to heavy metals causes raise of MDA concentration and causes greater increase in AOPP concentration than tobacco smoke.