Acetoaminophen-induced accumulation of 8-oxodeoxyguanosine through reduction of Ogg1 DNA repair enzyme in C6 glioma cells

Wan, Jie; Bae, Myung‐Ae; Song, Byoung–Joon

doi:10.1038/emm.2004.10

Cited by 31 publications

(14 citation statements)

References 31 publications

(43 reference statements)

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“…In addition, certain P450 enzymes such as CYP2E1 and CYP1A2, involved in the APAP metabolism, were degraded after administration of toxic doses of APAP (Snawder et al, 1994;Sinclair et al, 2000), possibly through interaction between these P450 proteins and NAPQI or other reactive metabolites produced from P450-mediated metabolism of APAP. Furthermore, we recently observed that APAP causes degradation of nuclear Ogg1, a DNA repair enzyme, without changing its mRNA level (Wan et al, 2004). By similar mechanisms, p53 may interact directly with NAPQI or other reactive metabolites of APAP (Supplemental Fig.…”

Section: Discussionmentioning

confidence: 94%

“…We previously reported that APAP can cause apoptosis (Bae et al, 2001) and oxidative DNA damage in C6 glioma cells (Wan et al, 2004). Therefore, we hypothesized that the level of p53 would be up-regulated by APAP, similar to the levels observed after exposure to chemotherapeutic agents and other DNA-damaging agents (Vogelstein et al, 2000), because APAP can induce apoptosis (Bae et al, 2001) and wild-type p53 is present in C6 glioma cells (Asai et al, 1994).…”

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confidence: 80%

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Ubiquitin-Dependent Degradation of p53 Protein Despite Phosphorylation at Its N Terminus by Acetaminophen

Lee

Wan²,

Kim³

et al. 2005

J Pharmacol Exp Ther

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We previously reported that acetaminophen (APAP, 4-hydroxyacetanilide) caused apoptosis of C6 glioma cells. Therefore, we hypothesized that the level of p53, which usually stimulates apoptosis, might be increased after APAP exposure. However, APAP exposure for 24 h markedly decreased the p53 content and its downstream target p21 in a concentration-dependent manner. Reduction of p53 was not accompanied by a decrease in p53 mRNA in C6 glioma cells, suggesting that p53 was mainly affected at the protein level. Unexpectedly, APAP stimulated phosphorylation of p53 at Ser15, Ser20, and Ser37, which usually elevates p53 content. However, phosphorylation of these residues did not prevent APAP-induced decrease in p53. The p53 reduction was independent from the level of phospho-Akt, which is known to promote p53 degradation. Immunoblot analysis of the immunoprecipitated p53 revealed that increased amounts of murine double minute 2 (mdm2) and ubiquitin were bound to p53 during its degradation. Lactacystin and N-benzoyloxycarbonyl (Z)-Leu-Leu-leucinal (MG132), inhibitors of proteasomal proteolysis, prevented the decrease, supporting the proteasomal degradation of p53 upon APAP exposure. Pretreatment with chlormethiazole, an inhibitor of ethanol-inducible CYP2E1, significantly lowered the CYP2E1 enzyme activity and the rate of APAP-induced cell death while it prevented the reduction of p53 and p21 in C6 glioma cells. A nontoxic analog of APAP, 3-hydroxyacetanilde, did not reduce p53 and p21 contents in C6 glioma cells and LLC-PK1 porcine kidney cells. Taken together, our results show that APAP or its reactive metabolite(s) can directly reduce the p53 content through mdm2-mediated ubiquitin conjugation, despite phosphorylation of p53 at its N terminus.

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Section: Discussionmentioning

confidence: 94%

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confidence: 80%

Ubiquitin-Dependent Degradation of p53 Protein Despite Phosphorylation at Its N Terminus by Acetaminophen

Lee

Wan²,

Kim³

et al. 2005

J Pharmacol Exp Ther

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“…The deletion and/or mutation through nitroxidative modifications of mitochondrial DNA can exert deleterious effects accompanied with increased amounts of ROS leakage, since mitochondrial DNA encode 13 polypeptides, all of which are subunits of the four mitochondrial ETC proteins [176, 177]. In addition, mitochondrial DNA and proteins are more susceptible to nitroxidative damage due to the absence of protective antioxidant protein catalase, the low activity of DNA repair enzymes, and the absence of histones and polyamines [178]. The damage of mitochondrial DNA, which is essential for normal formation of the ETC components, and inefficient repair are thought to be important in both alcohol- and HFD-induced hepatic cellular damage [179–182].…”

Section: Increased Cyp2e1 Levels and The Resultant Nitroxidative Strementioning

confidence: 99%

Role of CYP2E1 in Mitochondrial Dysfunction and Hepatic Injury by Alcohol and Non-Alcoholic Substances

Abdelmegeed

Choi

et al. 2017

CMP

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Alcoholic fatty liver diseases (AFLD) and non-alcoholic fatty liver diseases (NAFLD) are two pathological conditions that are spreading worldwide. Both conditions are remarkably similar with regards to the pathophysiological mechanism and progression despite different causes. Oxidative stress-induced mitochondrial dysfunction through post-translational protein modifications and/or mitochondrial DNA damage has been a major risk factor in both AFLD and NAFLD development and progression. Cytochrome P450-2E1 (CYP2E1), a known important inducer of oxidative radicals in the cells, has been reported to remarkably increase in both AFLD and NAFLD. Interestingly, CYP2E1 isoforms expressed in both endoplasmic reticulum (ER) and mitochondria, likely lead to the deleterious consequences in response to alcohol or in conditions of NAFLD after exposure to high fat diet (HFD) and in obesity and diabetes. Whether CYP2E1 in both ER and mitochondria work simultaneously or sequentially in various conditions and whether mitochondrial CYP2E1 may exert more pronounced effects on mitochondrial dysfunction in AFLD and NAFLD are unclear. The aims of this review are to briefly describe the role of CYP2E1 and resultant oxidative stress in promoting mitochondrial dysfunction and the development or progression of AFLD and NAFLD, to shed a light on the function of the mitochondrial CYP2E1 as compared with the ER-associated CYP2E1. We finally discuss translational research opportunities related to this field.

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“…Mitochondrial DNA is also extremely sensitive to nitroxidative damage due to its location within the cell close to the inner mitochondrial membrane, and the relatively low levels of protective antioxidant enzymes, histone proteins, or polyamines and DNA repair enzymes in mitochondria compared to other subcellular organelles including nuclei ([138, 181] and references therein). In addition, it has been suggested that the rate of mutation in mitochondrial DNA is 10-fold higher than that in the nuclear DNA [182].…”

Section: Protein Nitration In Mitochondria and Potential Consequenmentioning

confidence: 99%

Functional Roles of Protein Nitration in Acute and Chronic Liver Diseases

Abdelmegeed

Song

2014

Oxidative Medicine and Cellular Longevity

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Nitric oxide, when combined with superoxide, produces peroxynitrite, which is known to be an important mediator for a number of diseases including various liver diseases. Peroxynitrite can modify tyrosine residue(s) of many proteins resulting in protein nitration, which may alter structure and function of each target protein. Various proteomics and immunological methods including mass spectrometry combined with both high pressure liquid chromatography and 2D PAGE have been employed to identify and characterize nitrated proteins from pathological tissue samples to determine their roles. However, these methods contain a few technical problems such as low efficiencies with the detection of a limited number of nitrated proteins and labor intensiveness. Therefore, a systematic approach to efficiently identify nitrated proteins and characterize their functional roles is likely to shed new insights into understanding of the mechanisms of hepatic disease pathophysiology and subsequent development of new therapeutics. The aims of this review are to briefly describe the mechanisms of hepatic diseases. In addition, we specifically describe a systematic approach to efficiently identify nitrated proteins to study their causal roles or functional consequences in promoting acute and chronic liver diseases including alcoholic and nonalcoholic fatty liver diseases. We finally discuss translational research applications by analyzing nitrated proteins in evaluating the efficacies of potentially beneficial agents to prevent or treat various diseases in the liver and other tissues.

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Acetoaminophen-induced accumulation of 8-oxodeoxyguanosine through reduction of Ogg1 DNA repair enzyme in C6 glioma cells

Cited by 31 publications

References 31 publications

Ubiquitin-Dependent Degradation of p53 Protein Despite Phosphorylation at Its N Terminus by Acetaminophen

Ubiquitin-Dependent Degradation of p53 Protein Despite Phosphorylation at Its N Terminus by Acetaminophen

Role of CYP2E1 in Mitochondrial Dysfunction and Hepatic Injury by Alcohol and Non-Alcoholic Substances

Functional Roles of Protein Nitration in Acute and Chronic Liver Diseases

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