Ethanol Lowers Glutathione in Rat Liver and Brain and Inhibits Methionine Synthase in a Cobalamin-Dependent Manner

Waly, Mostafa I.; Kharbanda, Kusum K.; Deth, Richard C.

doi:10.1111/j.1530-0277.2010.01343.x

Cited by 27 publications

(27 citation statements)

References 45 publications

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“…TCAH is a highly reactive aldehyde that has been proposed to spontaneously condense with the biogenic amine tryptamine to produce an alkaloid-type neurotoxin (Bringmann et al ., 1990). Our lab has studied the ability of TCAH extensively to form adducts with T cells and promote their activation in vitro and in vivo (Blossom et al, 2004; Blossom et al, 2006a; Blossom et al, 2006b; Blossom et al, 2007b; Gilbert et al, 2004) The ability of reactive aldehydes (i.e., from ethanol metabolism) to inhibit methionine synthase activity and subsequently lower glutathione has been documented (Waly et al ., 2011; Waly et al ., 2004). Decreased methionine synthase activity would therefore result in an accumulation of SAH and inhibition of SAM, and a depletion of GSH similar to what is observed in our model.…”

Section: Discussionmentioning

confidence: 99%

Postnatal exposure to trichloroethylene alters glutathione redox homeostasis, methylation potential, and neurotrophin expression in the mouse hippocampus

et al. 2012

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Previous studies have shown that continuous exposure throughout gestation until the juvenile period to environmentally-relevant doses of trichloroethylene (TCE) in the drinking water of MRL+/+ mice promoted adverse behavior associated with glutathione depletion in the cerebellum indicating increased sensitivity to oxidative stress. The purpose of this study was to extend our findings and further characterize the impact of TCE exposure on redox homeostasis and biomarkers of oxidative stress in the hippocampus, a brain region prone to oxidative stress. Instead of a continuous exposure, the mice were exposed to water only or two environmentally relevant doses of TCE in the drinking water postnatally from birth until 6 weeks of age. Biomarkers of plasma metabolites in the transsulfuration pathway and the transmethylation pathway of the methionine cycle were also examined. Gene expression of neurotrophins was examined to investigate a possible relationship between oxidative stress, redox imbalance and neurotrophic factor expression with TCE exposure. Our results show that hippocampi isolated from male mice exposed to TCE showed altered glutathione redox homeostasis indicating a more oxidized state. Also observed was a significant, dose dependent increase in glutathione precursors. Plasma from the TCE treated mice showed alterations in metabolites in the transsulfuration and transmethylation pathways indicating redox imbalance and altered methylation capacity. 3-Nitrotyrosine, a biomarker of protein oxidative stress, was also significantly higher in plasma and hippocampus of TCE-exposed mice compared to controls. In contrast, expression of key neurotrophic factors in the hippocampus (BDNF, NGF, and NT-3) was significantly reduced compared to controls. Our results demonstrate that low-level postnatal and early life TCE exposure modulates neurotrophin gene expression in the mouse hippocampus and may provide a mechanism for TCE-mediated neurotoxicity.

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Section: Discussionmentioning

confidence: 99%

Postnatal exposure to trichloroethylene alters glutathione redox homeostasis, methylation potential, and neurotrophin expression in the mouse hippocampus

et al. 2012

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“…Co-existence of NO and superoxide anion can generate more cytotoxic agents, peroxynitrite (ONOO-) and peroxynitrous acid (ONOOH), both of which have been implicated in neuronal cell death (Brown, 2010; Chung and David, 2010; Franco et al, 2013; Gould et al, 2013; Maggio et al, 2012; Malinski, 2007; Schildknecht et al, 2013). Since the brain contains relatively low amounts of glutathione (GSH) and other energy substrates compared to other peripheral tissues, including the liver (Aoyama and Nakaki, 2013; Wali et al, 2011), it is relatively sensitive to severe nitroxidative damage.…”

Section: Consequences Of Increased Nitroxidative Stressmentioning

confidence: 99%

Mitochondrial dysfunction and cell death in neurodegenerative diseases through nitroxidative stress

et al. 2016

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Mitochondria are important for providing cellular energy ATP through the oxidative phosphorylation pathway. They are also critical in regulating many cellular functions including the fatty acid oxidation, the metabolism of glutamate and urea, the anti-oxidant defense, and the apoptosis pathway. Mitochondria are an important source of reactive oxygen species leaked from the electron transport chain while they are susceptible to oxidative damage, leading to mitochondrial dysfunction and tissue injury. In fact, impaired mitochondrial function is commonly observed in many types of neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, alcoholic dementia, brain ischemia-reperfusion related injury, and others, although many of these neurological disorders have unique etiological factors. Mitochondrial dysfunction under many pathological conditions is likely to be promoted by increased nitroxidative stress, which can stimulate post-translational modifications (PTMs) of mitochondrial proteins and/or oxidative damage to mitochondrial DNA and lipids. Furthermore, recent studies have demonstrated that various antioxidants, including naturally occurring flavonoids and polyphenols as well as synthetic compounds, can block the formation of reactive oxygen and/or nitrogen species, and thus ultimately prevent the PTMs of many proteins with improved disease conditions. Therefore, the present review is aimed to describe the recent research developments in the molecular mechanisms for mitochondrial dysfunction and tissue injury in neurodegenerative diseases and discuss translational research opportunities.

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“…In light of the influence of redox on methylation of DNA (and histones), the ability of morphine to modulate GSH/GSSG and SAM/SAH provides an example of how epigenetic status can be altered by drugs of abuse. Alcohol induces similar effects by lowering GSH levels and impairing methylation (Waly et al, 2011), whereas cocaine , amphetamine (Carvalho et al, 2001), and heroin (Gutowicz et al, 2011) also alter GSH levels. Although our results implicate MOR-mediated regulation of EAAT3 as the proximal event for morphine-induced changes in DNA methylation, other drugs of abuse may produce redox changes via uniquely different mechanisms.…”

Section: Morphine-induced Epigenetic Changes Via Eaat3mentioning

confidence: 99%

“…Although our results implicate MOR-mediated regulation of EAAT3 as the proximal event for morphine-induced changes in DNA methylation, other drugs of abuse may produce redox changes via uniquely different mechanisms. Notably, alcohol potently decreases EAAT3 activity via a protein kinase C-dependent pathway (Kim et al, 2003) and inhibits MS activity (Waly et al, 2011). Similarly, nicotine inhibits EAAT3 activity via the PKC pathway (Yoon et al, 2014).…”

Section: Morphine-induced Epigenetic Changes Via Eaat3mentioning

confidence: 99%

“…1. Alternatively, HCY can be converted to methionine via the activity of methionine synthase (MS), and MS activity is dependent upon the GSH-based redox status of the cell (Waly et al, 2011). Methionine is a precursor for S-adenosylmethionine (SAM), which donates methyl groups for more than 250 methylation reactions, and is subsequently converted to S-adenosylhomocysteine (SAH) upon methyl group donation (Cheng and Blumenthal, 1999).…”

Section: Introductionmentioning

confidence: 99%

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Morphine Induces Redox-Based Changes in Global DNA Methylation and Retrotransposon Transcription by Inhibition of Excitatory Amino Acid Transporter Type 3–Mediated Cysteine Uptake

et al. 2014

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Canonically, opioids influence cells by binding to a G proteincoupled opioid receptor, initiating intracellular signaling cascades, such as protein kinase, phosphatidylinositol 3-kinase, and extracellular receptor kinase pathways. This results in several downstream effects, including decreased levels of the reduced form of glutathione (GSH) and elevated oxidative stress, as well as epigenetic changes, especially in retrotransposons and heterochromatin, although the mechanism and consequences of these actions are unclear. We characterized the acute and long-term influence of morphine on redox and methylation status (including DNA methylation levels) in cultured neuronal SH-SY5Y cells. Acting via m-opioid receptors, morphine inhibits excitatory amino acid transporter type 3-mediated cysteine uptake via multiple signaling pathways, involving different G proteins and protein kinases in a temporal manner. Decreased cysteine uptake was associated with decreases in both the redox and methylation status of neuronal cells, as defined by the ratios of GSH to oxidized forms of glutathione and S-adenosylmethionine to S-adenosylhomocysteine levels, respectively. Further, morphine induced global DNA methylation changes, including CpG sites in long interspersed nuclear elements (LINE-1) retrotransposons, resulting in increased LINE-1 mRNA. Together, these findings illuminate the mechanism by which morphine, and potentially other opioids, can influence neuronal-cell redox and methylation status including DNA methylation. Since epigenetic changes are implicated in drug addiction and tolerance phenomenon, this study could potentially extrapolate to elucidate a novel mechanism of action for other drugs of abuse.

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Ethanol Lowers Glutathione in Rat Liver and Brain and Inhibits Methionine Synthase in a Cobalamin-Dependent Manner

Cited by 27 publications

References 45 publications

Postnatal exposure to trichloroethylene alters glutathione redox homeostasis, methylation potential, and neurotrophin expression in the mouse hippocampus

Postnatal exposure to trichloroethylene alters glutathione redox homeostasis, methylation potential, and neurotrophin expression in the mouse hippocampus

Mitochondrial dysfunction and cell death in neurodegenerative diseases through nitroxidative stress

Morphine Induces Redox-Based Changes in Global DNA Methylation and Retrotransposon Transcription by Inhibition of Excitatory Amino Acid Transporter Type 3–Mediated Cysteine Uptake

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