The Val16Ala-SOD2 polymorphism affects cyto-genotoxicity of pyridostigmine bromide on human peripheral blood mononuclear cells

Azzolin, Verônica Farina; Barbisan, Fernanda; Teixeira, Cibele Ferreira; Pillar, Danieli Monteiro; Mastella, Moisés Henrique; Duarte, Thiago; Turra, Bárbara Osmarin; Ribeiro, Euler Esteves; Duarte, Marta Maria Frescura Medeiros; Cruz, Ivana Beatrice Mânica da

doi:10.1016/j.tiv.2019.06.004

Cited by 4 publications

(5 citation statements)

References 38 publications

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“…In the present study, G allele carriers with high Cd exposure was associated with much higher NTD risk when compared to fetuses who did not carry G alleles, suggesting the modification effect of this SNP on the NTD risk in association with Cd exposure. This result was consistent with another study, in which peripheral blood mononuclear cells (PBMCs) derived from people with GG genotype showed higher sensitivity to pyridostigmine bromide (PB)-induced oxidative stress [43]. On the other…”

Section: Discussionsupporting

confidence: 92%

Associations between prenatal exposure to cadmium and lead with neural tube defect risks are modified by single-nucleotide polymorphisms of fetal MTHFR and SOD2: a case–control study

Liu

et al. 2021

Environ Health

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Background Prenatal exposure to heavy metals is implicated in the etiology of birth defects. We investigated whether concentrations of cadmium (Cd) and lead (Pb) in umbilical cord tissue are associated with risk for neural tube defects (NTDs) and whether selected genetic variants of the fetus modify their associations. Methods This study included 166 cases of NTD fetuses/newborns and 166 newborns without congenital malformations. Umbilical cord tissue was collected at birth or elective pregnancy termination. Cd and Pb concentrations were assessed by inductively coupled plasma-mass spectrometry, and 20 single-nucleotide polymorphisms (SNPs) in 9 genes were genotyped. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to estimate the risk for NTDs in association with metal concentrations or genotype using logistic regression. Multiplicative-scale interactions between the metals and genotypes on NTD risk were assessed with logistic regression, and additive-scale interactions were estimated with a non-linear mixed effects model. Results Higher concentrations of Cd were observed in the NTD group than in the control group, but no difference was found for Pb. Concentrations of Cd above the median level showed a risk effect, while the association between Pb and NTD risk was not significant in univariate analyses. The association of Cd was attenuated after adjusting for periconceptional folic acid supplementation. Fetuses with the AG and GG genotypes of rs4880 in SOD2 (superoxide dismutase 2) tended to have a lower risk, but fetuses with the CT and TT genotypes of rs1801133 in MTHFR (5,10-methylenetetrahydrofolatereductase) have a higher risk for NTDs when compared to their respective wild-type. rs4880 and Cd exhibited a multiplicative-scale interaction on NTD risk: the association between higher Cd and the risk for NTDs was increased by over fourfold in fetuses carrying the G allele [OR 4.43 (1.30–15.07)] compared to fetuses with the wild-type genotype. rs1801133 and Cd exposure showed an additive interaction, with a significant relative excess risk of interaction [RERI 0.64 (0.02–1.25)]. Conclusions Prenatal exposure to Cd may be a risk factor for NTDs, and the risk effect may be enhanced in fetuses who carry the G allele of rs4880 in SOD2 and T allele of rs1801133 in MTHFR.

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Section: Discussionsupporting

confidence: 92%

Associations between prenatal exposure to cadmium and lead with neural tube defect risks are modified by single-nucleotide polymorphisms of fetal MTHFR and SOD2: a case–control study

Liu

et al. 2021

Environ Health

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“…In this case, cells with higher basal production of H2O2 had higher cytotoxic sensitivity to CP, while cells with higher basal production of O 2− anion showed higher resistance to inhibition of AChE enzyme. These results suggest a potential pharmacogenetic effect of S-HP imbalance on BP efficacy and safety [95].…”

Section: Discussionmentioning

confidence: 71%

“…These results found in the literature suggest that the efficacy and toxicity to CP are influenced by the interaction with oxidative imbalance by Val16Ala-SOD2 polymorphism, indicating potential toxicogenetic and pharmacogenetic effects of this drug. The data presented here may potentially contribute to elucidate the interaction between BP and oxidative stress-inducing agents and may also be relevant to the clinical and epidemiological field related to the use of AChE inhibitors as therapeutic agents [94,95].…”

Section: Discussionmentioning

confidence: 92%

Interaction between Pyridostigmine Bromide and Oxidative Stress

Azzolin¹,

Barbisan²,

Jung³

et al. 2021

Medical Toxicology

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In this chapter the following topics will be addressed: (1) actions of the cholinergic system in the nervous system, commenting on acetylcholine metabolism and acetylcholinesterase metabolism; (2) acetylcholinesterase inhibitors as subtitle in this topic: pharmacological characterization of pyridostigmine bromide, mechanism of action, and therapeutic effect of the drug; (3) use of pyridostigmine bromide in Persian Gulf War; and (4) potential effect of pyridostigmine bromide in oxidative stress, addressing as subtitle the influence of pyridostigmine bromide on the superoxide-hydrogen peroxide imbalance model. Studies indicate that the interaction between pyridostigmine bromide and stressors could trigger genotoxicity, the mechanism associated with the induction of oxidative stress that leads to this side effect of this drug; however, this discussion needs to be better elucidated and may be more discussed as there is interaction between the pyridostigmine bromide and an endogenous oxidative imbalance caused by it or even by the possible interaction of this with genetic variations present in the antioxidant metabolism.

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“…These findings are in line with the report of Cui et al ( 15 ) suggesting that SOD2 AA16 genotype increase the risk for MCS, even if no correlation with biochemical features were assessed. Notably, it has been reported that this genotype increases the susceptibility to oxidative stress-related cyto-genotoxicity induced by pyridostigmine bromide, that has been implicated as a causal factor in Gulf War syndrome, a disorder sharing several features with MCS ( 44 ). Moreover, cytotoxic effects, at all times of exposure to static magnetic field (SMF), have been observed in peripheral blood mononuclear cells isolated from individuals bearing the AA16 genotype, while AV and VV cells presented mortality only after longer times of exposure to SMF.…”

Section: Discussionmentioning

confidence: 99%

Influence of the SOD2 A16V gene polymorphism on alterations of redox markers and erythrocyte membrane fatty acid profiles in patients with multiple chemical sensitivity

Cannata

Luca²,

Andolina

et al. 2021

Biomed Rep

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Chronically increased oxidative stress has been reported in patients with multiple chemical sensitivity (MCS). Recently, a single nucleotide polymorphism of the gene coding for mitochondrial superoxide dismutase (SOD2), namely the missense substitution A16V (C47>T) resulting in alteration of SOD2 enzyme activity, has been reported to be associated with MCS. However, the influence of SOD2 A16V genetic background on redox status of patients with MCS has not yet been investigated. Here, the results of a retrospective analysis aimed to evaluate the role of the SOD2 A16V polymorphism in the alterations of antioxidant defense markers as well as fatty acid (FA) composition of erythrocyte membranes in 67 patients with MCS matched with 55 healthy controls is reported. The mutated SOD2 V16 variant was observed more frequently in the MCS group compared with the control group, and this difference was statistically significant. The most common genotype in both groups was the heterozygous SOD2 AV16 variant, whereas the mutated SOD2 VV16 variant was more frequently observed in the MCS group, although the difference was not significant. The MCS cohort showed significantly depleted levels of plasma total antioxidant activity, ubiquinol, erythrocyte reduced glutathione and membrane polyunsaturated FA levels, coupled with significant increases in glutathione peroxidase activity, likely accounting for sustained detoxification from lipoperoxides. Notably, the highest levels of oxidative stress were found in patients with MCS bearing the genotype SOD2 AA16, whereas intermediate levels were found in patients bearing the heterozygous AV16 genotype. Healthy subjects bearing the SOD2 AA16 genotype also showed increased oxidative stress compared with carriers of other SOD2 genotypes. Despite the need for further confirmations in larger cohorts, due to MCS population genetic heterogeneity, these preliminary findings suggest that SOD2 defective activity makes certain patients with MCS more susceptible to developing oxidative stress following a chronic daily exposure to pro-oxidant insults.

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The Val16Ala-SOD2 polymorphism affects cyto-genotoxicity of pyridostigmine bromide on human peripheral blood mononuclear cells

Cited by 4 publications

References 38 publications

Associations between prenatal exposure to cadmium and lead with neural tube defect risks are modified by single-nucleotide polymorphisms of fetal MTHFR and SOD2: a case–control study

Associations between prenatal exposure to cadmium and lead with neural tube defect risks are modified by single-nucleotide polymorphisms of fetal MTHFR and SOD2: a case–control study

Interaction between Pyridostigmine Bromide and Oxidative Stress

Influence of the SOD2 A16V gene polymorphism on alterations of redox markers and erythrocyte membrane fatty acid profiles in patients with multiple chemical sensitivity

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