Upregulation of CYP2E1 expression causes oxidative damage induced by 2-chloroethanol in primary cultured rat astrocytes

Tang, Hongge; Sun, Qi; Wang, Tong; Liao, Yingjun; Wang, Gaoyang; Zhao, Fenghong; Jin, Yaping

doi:10.1016/j.neuro.2019.09.016

Cited by 11 publications

(4 citation statements)

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“…It has been reported that CYP2E1 can convert 1,2-DCE into 2-CE, chloroacetaldehyde and chloroacetic acid [38][39][40][41]. Because of the high oxidase activity, CYP2E1-mediated metabolism of 1,2-DCE and its intermediates can lead to the generation of ROS, as a consequence induce oxidative damage in the brain [20,33] The present results revealed that CYP2E1 knockdown reversed 2-CE-induced augmentation of ROS production and A1s induction, suggesting that ROS production is involved in A1 activation. Using the ROS scavenger NAC, we further determined that ROS induce A1s.…”

Section: Discussionmentioning

confidence: 99%

A1 Reactive Astrocytes Activated by 2-chloroethanol Modulate M1 Microglia Polarization through Upregulating IL-1β and TNF-α

Wang

Sun

Tang

et al. 2021

Preprint

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Background1,2-Dichloroethane (1,2-DCE) is a synthetic organic chemical that causes brain edema under subacute poisoning. Our previous studies indicated that the neuroinflammation could be induced due to activation of both astrocytes and microglia during the course of brain edema in 1,2-DCE intoxicated mice. However, the crosstalk between the two glial cells in 1,2-DCE-induced neuroinflammation is unclear. In the current studies, we hypothesized that astrocytes are the first responder to the effects of 1,2-DCE in the brain, as they adhere to the cerebral capillaries, and they are an essential component of the blood-brain barrier (BBB).MethodsWe used primary cultured rat astrocytes and microglia, as well as a highly aggressively proliferating immortalized (HAPI) microglia cell line to study the effects of astrocytes on microglia polarization following exposure to 2-CE. ResultsFindings from the present studies demonstrated that treatment of primary rat astrocytes with 2-chloroethanol (2-CE), the intermediate metabolite of 1,2-DCE in vivo, can stimulate the activation of A1 reactive astrocytes (A1s) through p38 mitogen-activated protein kinase (p38 MAPK)/ nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) signaling pathways by the reactive oxygen species (ROS) produced during 2-CE metabolism. A1s activated by 2-CE can upregulate the expression of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and inducible nitric oxide synthase (iNOS), and stimulate the M1 polarization of microglia through IL-1β and TNF-α released by 2-CE activated A1s. Microglia are less sensitive to 2-CE than astrocytes, since treatment of primary rat microglia with 30 mM 2-CE alone failed to activate them, though this dose of 2-CE can activate A1s and in turn stimulate M1 polarization of microglia through the factors released by A1s. ConclusionThe neuroinflammation induced by 1,2-DCE in the brain of mice is most probably triggered by the activation of astrocytes. The understanding of the multidimensional roles of reactive astrocytes may further the development of new treatment strategies in reducing neuroinflammation and brain edema following 1,2-DCE-induced toxic encephalopathy.

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Section: Discussionmentioning

confidence: 99%

A1 Reactive Astrocytes Activated by 2-chloroethanol Modulate M1 Microglia Polarization through Upregulating IL-1β and TNF-α

Wang

Sun

Tang

et al. 2021

Preprint

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“…Heat shock protein 70 (HSP70) facilitates the synthesis of CYP2E1 proteins in the endoplasmic reticulum (ER) and their transfer into mitochondria ( Zhou et al, 2018 ). SP1, a ubiquitously expressed transcription factor, transcribes and activates CYP2E1 and HSP70 ( Morgan, 1989 ; Tang et al, 2019 ). Upon beta-sitosterol, DHM, naringenin, myricetin, kaempferol, emodin, and apigenin treatment, the levels of endogenous CYP2E1 were reduced in liver tissues, which attenuated hepatocyte injury ( Jayaraman and Namasivayam, 2011 ; Liu et al, 2014 ; Wang et al, 2017 ; Zhou et al, 2018 ; Chen Z. et al, 2020 ; Silva et al, 2020 ; Ahmad et al, 2022 ).…”

Section: Mechanism Of Action Of Hovenia Dulcis In the Treatment Of Al...mentioning

confidence: 99%

Hovenia dulcis: a Chinese medicine that plays an essential role in alcohol-associated liver disease

He,

Liu,

Wang

et al. 2024

Front. Pharmacol.

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Globally, alcohol-associated liver disease (ALD) has become an increased burden for society. Disulfirams, Benzodiazepines (BZDs), and corticosteroids are commonly used to treat ALD. However, the occurrence of side effects such as hepatotoxicity and dependence, impedes the achievement of desirable and optimal therapeutic efficacy. Therefore, there is an urgent need for more effective and safer treatments. Hovenia dulcis is an herbal medicine promoting alcohol removal clearance, lipid-lowering, anti-inflammatory, and hepatoprotective properties. Hovenia dulcis has a variety of chemical components such as dihydromyricetin, quercetin and beta-sitosterol, which can affect ALD through multiple pathways, including ethanol metabolism, immune response, hepatic fibrosis, oxidative stress, autophagy, lipid metabolism, and intestinal barrier, suggesting its promising role in the treatment of ALD. Thus, this work aims to comprehensively review the chemical composition of Hovenia dulcis and the molecular mechanisms involved in the process of ALD treatment.

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“…In a separate study, treatment with 2-chloroethanol induced the expression of CYP2E1 in rat brain and caused cytotoxicity in rat astrocytes with an enhanced level of ROS, MDA, and apoptotic cells. Increased levels of CYP2E1, ROS, MDA, apoptotic cells, and phosphorylated ERK1/2 (extracellular signal-regulated kinase1/2) were attenuated in rat astrocytes when pretreated with either diallyl sulfide (DAS) or vitamin C prior to exposure of 2-chloroethanol [ 91 ].…”

Section: Extrahepatic Cyp2e1 In Drug Interactions and Potential Treat...mentioning

confidence: 99%

Hepatic, Extrahepatic and Extracellular Vesicle Cytochrome P450 2E1 in Alcohol and Acetaminophen-Mediated Adverse Interactions and Potential Treatment Options

Kumar

Singla

Singh

et al. 2022

Cells

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Alcohol and several therapeutic drugs, including acetaminophen, are metabolized by cytochrome P450 2E1 (CYP2E1) into toxic compounds. At low levels, these compounds are not detrimental, but higher sustained levels of these compounds can lead to life-long problems such as cytotoxicity, organ damage, and cancer. Furthermore, CYP2E1 can facilitate or enhance the effects of alcohol-drug and drug-drug interactions. In this review, we discuss the role of CYP2E1 in the metabolism of alcohol and drugs (with emphasis on acetaminophen), mediating injury/toxicities, and drug-drug/alcohol-drug interactions. Next, we discuss various compounds and various nutraceuticals that can reduce or prevent alcohol/drug-induced toxicity. Additionally, we highlight experimental outcomes of alcohol/drug-induced toxicity and potential treatment strategies. Finally, we cover the role and implications of extracellular vesicles (EVs) containing CYP2E1 in hepatic and extrahepatic cells and provide perspectives on the clinical relevance of EVs containing CYP2E1 in intracellular and intercellular communications leading to drug-drug and alcohol-drug interactions. Furthermore, we provide our perspectives on CYP2E1 as a druggable target using nutraceuticals and the use of EVs for targeted drug delivery in extrahepatic and hepatic cells, especially to treat cellular toxicity.

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Upregulation of CYP2E1 expression causes oxidative damage induced by 2-chloroethanol in primary cultured rat astrocytes

Cited by 11 publications

References 41 publications

A1 Reactive Astrocytes Activated by 2-chloroethanol Modulate M1 Microglia Polarization through Upregulating IL-1β and TNF-α

A1 Reactive Astrocytes Activated by 2-chloroethanol Modulate M1 Microglia Polarization through Upregulating IL-1β and TNF-α

Hovenia dulcis: a Chinese medicine that plays an essential role in alcohol-associated liver disease

Hepatic, Extrahepatic and Extracellular Vesicle Cytochrome P450 2E1 in Alcohol and Acetaminophen-Mediated Adverse Interactions and Potential Treatment Options

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