Role of inhibiting Chk1-p53 pathway in hepatotoxicity caused by chronic arsenic exposure from coal-burning
Autor: | Chunyan Liu, Xiong Chen, Ma Lu, Dapeng Wang, Yuan Yang, Aihua Zhang, Tingting Xie |
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Rok vydání: | 2021 |
Předmět: |
0301 basic medicine
Sodium arsenite Health Toxicology and Mutagenesis Population Arsenic poisoning chemistry.chemical_element Apoptosis Pharmacology Toxicology Arsenic Heating 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Arsenic Poisoning medicine Animals Humans CHEK1 education education.field_of_study Plant Extracts Chemistry Ginkgo biloba General Medicine Pifithrin medicine.disease Rats Coal 030104 developmental biology 030220 oncology & carcinogenesis Checkpoint Kinase 1 Models Animal Hepatocytes Chemical and Drug Induced Liver Injury DNA Damage Phytotherapy Signal Transduction Toxicant |
Zdroj: | Human & Experimental Toxicology. 40:1141-1152 |
ISSN: | 1477-0903 0960-3271 |
Popis: | Arsenic is a naturally occurring environmental toxicant, chronic exposure to arsenic can cause multiorgan damage, except for typical skin lesions, liver damage is the main problem for health concern in population with arsenic poisoning. Abnormal apoptosis is closely related to liver-related diseases, and p53 is one of the important hallmark proteins in apoptosis progression. This study was to investigate whether arsenic poisoning-induced hepatocyte apoptosis and the underlying role of p53 signaling pathway. A rat model of arsenic poisoning was established by feeding corn powder for 90 days, which was baked with high arsenic coal, then were treated with Ginkgo biloba extract (GBE) for 45 days by gavage. The results showed that arsenic induced liver damage, increased hepatocyte apoptosis and elevated the expression level of Chk1 and the ratios of p-p53/p53 and Bax/Bcl-2 in liver tissues, which were significantly attenuated by GBE. Additionally, to further demonstrate the potential apoptosis-associated mechanism, L-02 cells were pre-incubated with p53 inhibitor pifithrin-α (PFTα), ataxia telangiectasia-mutated (ATM)/ataxia telangiectasia-mutated and Rad3-related (ATR) inhibitor (CGK733) or GBE, then treated with sodium arsenite (NaAsO2) for 24 h. The results showed that GBE, PFTα or CGK733 significantly reduced arsenic-induced Chk1 expression and the ratios of p-p53/p53 and Bax/Bcl-2. In conclusion, Chk1-p53 pathway was involved in arsenic poisoning-induced hepatotoxicity, and inhibiting of Chk1-p53 pathway ameliorated hepatocyte apoptosis caused by coal-burning arsenic poisoning. The study provides a pivotal clue for understanding of the mechanism of arsenic poisoning-induced liver damage, and possible intervention strategies. |
Databáze: | OpenAIRE |
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