Chemical toxicology of reactive species in the atmosphere: two decades of progress in an electron acceptor and an electrophile

Kumagai, Yoshito; Abiko, Yoshihiro; Cong, Nho Luong

doi:10.2131/jts.41.sp37

Cited by 9 publications

(5 citation statements)

References 97 publications

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“…Quinone compounds are ubiquitously diffused in the environment as elements of the food chains or as air pollutants, for example in the diesel exhaust particles 53 . Quinones can also be generated in the body as a result of some xenobiotic metabolism through the cytochrome P450 system 36 .…”

Section: Discussionmentioning

confidence: 99%

GSK3β is a key regulator of the ROS-dependent necrotic death induced by the quinone DMNQ

et al. 2020

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Signaling pathways controlling necrosis are still mysterious and debated. We applied a shRNA-based viability screen to identify critical elements of the necrotic response. We took advantage from a small molecule (G5) that makes covalent adducts with free thiols by Michael addition and elicits multiple stresses. In cells resistant to apoptosis, G5 triggers necrosis through the induction of protein unfolding, glutathione depletion, ER stress, proteasomal impairments, and cytoskeletal stress. The kinase GSK3β was isolated among the top hits of the screening. Using the quinone DMNQ, a ROS generator, we demonstrate that GSK3β is involved in the regulation of ROS-dependent necrosis. Our results have been validated using siRNA and by knocking-out GSK3β with the CRISPR/Cas9 technology. In response to DMNQ GSK3β is activated by serine 9 dephosphorylation, concomitantly to Akt inactivation. During the quinone-induced pronecrotic stress, GSK3β gradually accumulates into the nucleus, before the collapse of the mitochondrial membrane potential. Accumulation of ROS in response to DMNQ is impaired by the absence of GSK3β. We provide evidence that the activities of the obligatory two-electrons reducing flavoenzymes, NQO1 (NAD(P)H quinone dehydrogenase 1) and NQO2 are required to suppress DMNQ-induced necrosis. In the absence of GSK3β the expression of NQO1 and NQO2 is dramatically increased, possibly because of an increased transcriptional activity of NRF2. In summary, GSK3β by blunting the anti-oxidant response and particularly NQO1 and NQO2 expression, favors the appearance of necrosis in response to ROS, as generated by the quinone DMNQ.

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Section: Discussionmentioning

confidence: 99%

GSK3β is a key regulator of the ROS-dependent necrotic death induced by the quinone DMNQ

et al. 2020

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“…9,10-PQ have been determined in various air samples ( e.g ., 130–730 pg/m 3 in samples from Riverside, LA; 6.1 ng/m 3 in sample from Birmingham, UK) and a metabolite of 9,10-PQ was detected in urine from a nonsmoker living in the suburban area of Kanazawa, Japan, indicating the necessity for basic studies of the effects of 9,10-PQ in vivo and in vitro . In our previous study, we showed that exposure of mice to 9,10-PQ caused an enhancement of allergic airway inflammation and recruitment of inflammatory cells. , Additionally, intraperitoneal administration of 9,10-PQ significantly suppressed endothelium-dependent vasorelaxation of rat aorta by acetylcholine and also increased the blood pressure, indicating that 9,10-PQ is a key molecular toxicant among atmospheric pollutants that increases health risks through an oxidative stress-dependent mechanism involving 9,10-PQ redox cycling.…”

Section: Discussionmentioning

confidence: 99%

“…ROS oxidize protein thiols to sulfenic acid (P-SOH) groups, which can undergo further oxidation to yield sulfinic acid (P-SO 2 H) and sulfonic acid (P-SO 3 H), leading to functional changes of the modified proteins. , Our in vivo and in vitro experiments indicated that Trx1 is a potential target for S -oxidation by 9,10-PQ, forming inactive forms Trx1-S 2 or Trx1-SO n H. Ichijo and co-workers demonstrated that Trx1-(SH) 2 is a physiological inhibitor of ASK1. Thus, oxidation of Trx1 by ROS activates ASK1 upon dissociation of oxidized Trx1 from the Trx1–ASK1 complex, inducing apoptosis via the activation of ASK1–p38 signaling .…”

Section: Discussionmentioning

confidence: 99%

“…ROS derived from 9,10-PQ exposure enhance phosphorylation of p38, and overexpression of Trx1 suppresses intracellular oxidative stress initiated by 9,10-PQ. 9,10-PQ have been determined in various air samples (e.g., 130−730 pg/m 3 in samples from Riverside, LA; 1 6.1 ng/m 3 in sample from Birmingham, UK 26 ) 27 and a metabolite of 9,10-PQ was detected in urine from a nonsmoker living in the suburban area of Kanazawa, Japan, 28 indicating the necessity for basic studies of the effects of 9,10-PQ in vivo and in vitro. In our previous study, we showed that exposure of mice to 9,10-PQ caused an enhancement of allergic airway inflammation and recruitment of inflammatory cells.…”

Section: Discussionmentioning

confidence: 99%

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Redox Homeostasis is Disturbed by Redox Cycling between Reactive Cysteines of Thioredoxin 1 and 9,10-Phenanthrenequinone, an Atmospheric Electron Acceptor

Abiko

Taguchi

Hisamori

et al. 2022

Chem. Res. Toxicol.

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9,10-Phenanthrenequinone (9,10-PQ) is a toxicant in diesel exhaust particles and airborne particulate matter ≤2.5 μm in diameter. It is an efficient electron acceptor that readily reacts with dithiol compounds in vitro, resulting in the oxidation of thiol groups and concomitant generation of reactive oxygen species (ROS). However, it remains to be elucidated whether 9,10-PQ interacts with proximal protein dithiols. In the present study, we used thioredoxin 1 (Trx1) as a model of proteins with reactive proximal cysteines and examined whether it reacts with 9,10-PQ in cells and tissues, thereby affecting its catalytic activity and thiol status. Intratracheal injection of 9,10-PQ into mice resulted in protein oxidation and diminished Trx activity in the lungs. Using recombinant wild-type and C32S/C35S Trx1, we found that Cys32 and Cys35 selectively serve as electron donor sites for redox reactions with 9,10-PQ that lead to substantial inhibition of Trx activity. Addition of dithiothreitol restored the Trx activity inhibited by 9,10-PQ. Exposure of cultured cells to 9,10-PQ caused intracellular reactive oxygen species generation that led to protein oxidation, Trx1 dimerization, p38 phosphorylation, and apoptotic cell death. Overexpression of Trx1 blocked these 9,10-PQ-mediated events. These results suggest that the interaction of the reactive cysteines of Trx1 with 9,10-PQ causes oxidative stress, leading to disruption of redox homeostasis.

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“…Polycyclic aromatic hydrocarbons (PAHs) are both anthropogenic and naturally occurring ubiquitous environmental pollutants that are produced partly by combustion processes and are characterized by relatively high chemical stability. , Even so, they may be metabolically or abiotically converted to mutagenic quinone intermediates which are hazardous to human health. − Human exposure to quinones occurs through direct contact with oxidized PAHs in the environment, through metabolic formation of PAH- ortho -quinones, through the aldo-keto reductase pathway, and through drugs that possess quinone moieties. ,− …”

Section: Introductionmentioning

confidence: 99%

Formation of Bulky DNA Adducts by Non-Enzymatic Production of 1,2-Naphthoquinone-Epoxide from 1,2-Naphthoquinone under Physiological Conditions

Matsui

Yamada

Kuno

et al. 2019

Chem. Res. Toxicol.

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Quinones may be formed metabolically or abiotically from environmental pollutants and polycyclic aromatic hydrocarbons (PAHs); many are recognized as toxicological intermediates that cause a variety of deleterious cellular effects including mutagenicity. The PAH-o-quinone, 1,2-naphthoquinone (1,2-NQ), may exert its genotoxic effects through interactions with cellular nucleophiles such as DNA, however, the mechanisms of 1,2-NQ adduct formation are still under investigation. With the aim to further understand these mechanisms, the chemical structures of adducts formed from the reaction of 2′deoxyguanosine (dG) with 1,2-NQ under physiological conditions were investigated by liquid chromatography electrospray ionization tandem mass spectrometry and 1 H NMR analyses. Results showed that 1,2-NQ underwent non-enzymatic oxidation to form a 1,2-NQ-epoxide which in turn formed at least four bulky adducts with dG, and these adducts were more likely to be formed under physiological conditions. A mechanism was proposed whereby hydration of 1,2-NQ to form unstable naphthohydroquinones and 2-hydroxy-1,4-naphthoquinone resulted in formation of hydrogen peroxide that oxidized 1,2-NQ. These results suggest that the genotoxicity of 1,2-NQ may not only be caused through oxidative DNA damage and adduct formation through Michael addition but also through non-enzymatic oxidative transformation of 1,2-NQ itself to form an intermediate PAH-epoxide which covalently binds to DNA.

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Chemical toxicology of reactive species in the atmosphere: two decades of progress in an electron acceptor and an electrophile

Cited by 9 publications

References 97 publications

GSK3β is a key regulator of the ROS-dependent necrotic death induced by the quinone DMNQ

GSK3β is a key regulator of the ROS-dependent necrotic death induced by the quinone DMNQ

Redox Homeostasis is Disturbed by Redox Cycling between Reactive Cysteines of Thioredoxin 1 and 9,10-Phenanthrenequinone, an Atmospheric Electron Acceptor

Formation of Bulky DNA Adducts by Non-Enzymatic Production of 1,2-Naphthoquinone-Epoxide from 1,2-Naphthoquinone under Physiological Conditions

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