scholarly journals p53-mediated redox control promotes liver regeneration and maintains liver function in response to CCl4

2021 ◽  
Author(s):  
Timothy J. Humpton ◽  
Holly Hall ◽  
Christos Kiourtis ◽  
Colin Nixon ◽  
William Clark ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Reactive Oxygen Species ◽  
Transcription Factor ◽  
Cytochrome P450 ◽  
Carbon Tetrachloride ◽  
Damage Control ◽  
Oxygen Species ◽  
Redox Control ◽  
Reporter Mouse ◽  
Prognostic Utility

AbstractThe p53 transcription factor coordinates wide-ranging responses to stress that contribute to its function as a tumour suppressor. The responses to p53 induction are complex and range from mediating the elimination of stressed or damaged cells to promoting survival and repair. These activities of p53 can modulate tumour development but may also play a role in pathological responses to stress such as tissue damage and repair. Using a p53 reporter mouse, we have previously detected strong induction of p53 activity in the liver of mice treated with the hepatotoxin carbon tetrachloride (CCl4). Here, we show that p53 functions to support repair and recovery from CCl4-mediated liver damage, control reactive oxygen species (ROS) and limit the development of hepatocellular carcinoma (HCC), in part through the activation of a detoxification cytochrome P450, CYP2A5 (CYP2A6 in humans). Our work demonstrates an important role for p53-mediated redox control in facilitating the hepatic regenerative response after damage and identifies CYP2A5/CYP2A6 as a mediator of this pathway with potential prognostic utility in human HCC.

Estimation of the infl uence of cytochrome P450 induction on carbon tetrachloride genotoxicity in vitro

2019 ◽  
pp. 206-211
Author(s):  
E. R. Kudoyarov ◽  
D. D. Karimov ◽  
D. O. Karimov ◽  
E. F. Repina ◽  
A. B. Bakirov ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Cytochrome P450 ◽  
Carbon Tetrachloride ◽  
Culture Medium ◽  
Oxygen Species ◽  
Chemical Induction ◽  
Comet Tail ◽  
Cytochrome P450 Induction ◽  
Increased Activity

Introduction. One of the stages of the pathogenesis of the toxic eff ect of carbon tetrachloride is the formation of compounds of reactive oxygen species with DNA, leading to the modifi cation of nitrogenous bases. The frequency of formation of nucleotides modifi ed by nitrogenous bases correlates with the number of single-and double-chain breaks of deoxyribonucleic acid (DNA) molecules. The initiator of the formation of active forms of oxygen and lipid peroxidation in liver cells upon receipt of carbon tetrachloride is a trichloromethyl radical formed during biotransformation by microsomal enzymes of cytochrome P450.The aim of the study was to analyze the changes in the genotoxicity of carbon tetrachloride in hepatocytes at normal and increased activity of cytochrome P450 caused by the infl uence of an inductor (sovol).Materials and methods. Evaluation of genotoxicity is performed by the method of DNA-comets aft er gavage with carbon tetrachloride culture of mouse hepatocytes МН22а in 96-well microplates without the induction of cytochrome P450 and chemical induction of cytochrome P450 by sovol. Determination of DNA content in comet tail (%), comet tail length (μm) and tail moment was performed in ImageJ 1.48. Statistical analysis of the results was performed in the program SPSS Statistics 21.Results: Experimental data on the genotoxic eff ect of carbon tetrachloride on hepatocytes of the MN–22A cell line without induction of cytochrome P450 and chemical induction of cytochrome P450 by sovol are presented. It was found that 0.5 mm solution of carbon tetrachloride in 1 hour aft er addition to the culture medium is genotoxic for hepatocytes MH–22a without the use of sovol (p<0.001). Th e lack of determined using the method of DNA-comet signs of genotoxicity of 5 mm carbon tetrachloride (p>0.05) in the culture medium, probably due to the transition of the cells into a state of parametros. Genotoxic eff ect is not detected by DNA comet aft er 3 and 24 hours of incubation of hepatocytes MN–22A with 0.5 and 5 mm solutions of carbon tetrachloride without preincubation with sovol (p>0.05), which may indicate repair of the damage. Aft er 72 hours of preliminary incubation of hepatocytes with sovol and the followin g four-hour cell priming with 2.5 mm tetrachloromethane solution, higher values of the parameters of DNA comets are observed than when seeding with tetrachloromethane without incubation with sovol (p<0.05).Conclusions: According to the results of the study 72 hours of cytochrome P450 induction by sovol increases the genotoxicity of carbon tetrachloride in vitro, compared with 24 h of inductor exposure, which may indirectly indicate a higher level of formed reactive oxygen species caused by increased activity of cytochrome P450 enzymes. 

Epigenetic Changes Induced by Reactive Oxygen Species in Hepatocellular Carcinoma: Methylation of the E-cadherin Promoter

2008 ◽  
Vol 135 (6) ◽  
pp. 2128-2140.e8 ◽  
Author(s):  
Seung-Oe Lim ◽  
Jin-Mo Gu ◽  
Min Sook Kim ◽  
Hyun-Soo Kim ◽  
Young Nyun Park ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Reactive Oxygen Species ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Epigenetic Changes ◽  
E Cadherin

Involvement of reactive oxygen species in the metabolic pathways triggered by diesel exhaust particles in human airway epithelial cells

2003 ◽  
Vol 285 (3) ◽  
pp. L671-L679 ◽  
Author(s):  
Augustin Baulig ◽  
Michèle Garlatti ◽  
Véronique Bonvallot ◽  
Alexandre Marchand ◽  
Robert Barouki ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Transcription Factor ◽  
Epithelial Cells ◽  
Diesel Exhaust ◽  
Diesel Exhaust Particles ◽  
Ros Production ◽  
Oxygen Species ◽  
Expression Of Genes ◽  
Exhaust Particles ◽  
Nrf2 Transcription Factor

Diesel exhaust particles (DEP) induce a proinflammatory response in human bronchial epithelial cells (16HBE) characterized by the release of proinflammatory cytokines after activation of transduction pathways involving MAPK and the transcription factor NF-κB. Because cellular effects induced by DEP are prevented by antioxidants, they could be mediated by reactive oxygen species (ROS). Using fluorescent probes, we detected ROS production in bronchial and nasal epithelial cells exposed to native DEP, organic extracts of DEP (OE-DEP), or several polyaromatic hydrocarbons. Carbon black particles mimicking the inorganic part of DEP did not increase ROS production. DEP and OE-DEP also induced the expression of genes for phase I [cytochrome P-450 1A1 (CYP1A1)] and phase II [NADPH quinone oxidoreductase-1 (NQO-1)] xenobiotic metabolization enzymes, suggesting that DEP-adsorbed organic compounds become bioavailable, activate transcription, and are metabolized since the CYP1A1 enzymatic activity is increased. Because NQO-1 gene induction is reduced by antioxidants, it could be related to the ROS generated by DEP, most likely through the activation of the stress-sensitive Nrf2 transcription factor. Indeed, DEP induced the translocation of Nrf2 to the nucleus and increased protein nuclear binding to the antioxidant responsive element. In conclusion, we show that DEP-organic compounds generate an oxidative stress, activate the Nrf2 transcription factor, and increase the expression of genes for phase I and II metabolization enzymes.

scholarly journals Reactive Oxygen Species-Mediated Cezanne Inactivation by Oxidation of its Catalytic Cysteine Residue in Hepatocellular Carcinoma

2019 ◽  
Vol 27 (9) ◽  
pp. 1069-1077
Author(s):  
Zhongyuan Yin ◽  
Lin Yang ◽  
Feng Wu ◽  
Jinshuo Fan ◽  
Juanjuan Xu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Reactive Oxygen Species ◽  
Reactive Oxygen ◽  
Matrix Metalloproteinase 2 ◽  
Intercellular Adhesion Molecule ◽  
Oxygen Species ◽  
Cysteine Oxidation ◽  
Diphenylene Iodonium ◽  
Hcc Cells ◽  
Inflammatory Effect

Cysteine oxidation occurs at the active site of deubiquitinases (DUBs) during many biologic signaling cascades. Here we report that hepatocellular carcinoma cells (HCCs) generated higher levels of endogenous reactive oxygen species (ROS). This elevated ROS production was inhibited by NADPH oxidase inhibitor diphenylene iodonium (DPI) and mitochondria electron chain inhibitor rotenone in HCC cells. Moreover, we found that H2O2 could activate NF-κB-dependent inflammatory effect through increased induction of matrix metalloproteinase 2 (MMP2), MMP9, and intercellular adhesion molecule 1 (ICAM1) expression levels. In addition, we found that H2O2 could prolong NF-κB activation by suppressing the negative regulatory functions of Cezanne in HCC cells. Ubiquitin-derived thiol-reactive probe (HA-UbVME) assay and biotin-tagged 1,3-cyclohexadione derivative (DCP-Bio1) assay showed that H2O2 has the capacity to inhibit the catalytic activity of Cezanne, and the reducing agent, DTT, could reactivate the Cezanne deubiquitinating enzyme activity. Taken all together, these findings demonstrated an important role for oxidation of Cezanne by ROS in regulation of the inflammatory effect of hepatocellular carcinoma.

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