Molecular & Cellular Toxicology
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2021
·Vol. 17
·期 2
·161-168
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IF 1.08
Chang Yicong,He Jingshan,Ma Bingke,Ishfaq Muhammad,Wang Jiaqi,Zhang Ruichen,Yuan Liang,Liu Jiarui,Li Changwen,Liu Fangping
Background Glutathione S-transferase A1 (GSTA1) is a detoxification enzyme and a sensitive marker for hepatotoxicity. We investigated the effects of JNK inhibition on different degrees of Acetaminophen (APAP)-induced hepatocyte injury and GSTA1 expression. Objective This study aimed to investigate the role of JNK signaling pathway in APAP-induced different degrees of hepatocyte injury and its correlation with GSTA1 by inhibiting the phosphorylation of JNK by SP600125. Results 6 and 8 mM APAP induced different degrees of hepatocyte injury and apoptosis, both activated JNK signaling pathway. In contrast, JNK inhibitor significantly reduced activation of JNK and c-JUN on exposure to APAP. Meanwhile, the levels of hepatocyte injury, oxidative stress, and apoptosis obviously decreased. Importantly, GSTA1 expression was significantly increased by JNK inhibition. Conclusions JNK inhibition attenuates APAP-induced hepatocyte injury and oxidative stress and increases GSTA1 expression. Furthermore, GSTA1 may be involved in this signaling pathway for detoxification.
研究领域:
药理学
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毒理学
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肝脏病学
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高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
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2026
·
IF 5.2
Tao Liu,Xu Zhang,Wei Zhang,Dejin Yang,Jipeng Li,Lin Liu
Objective α-Amanitin (α-AMA), the principal toxin of lethal mushrooms, induces severe liver injury by exacerbating oxidative stress. Glutathione S-transferase A1 (GSTA1), a crucial hepatic antioxidant enzyme, plays an ambiguous role in this process. Methods A mouse model of α-AMA-induced liver injury was established. Hepatic damage was assessed via serum biochemistry (ALT, AST, T-BIL) and histopathology (H&E staining). Oxidative stress markers (SOD, CAT, MDA) were measured. Integrated transcriptomics and metabolomics were employed to identify critical pathways. The interaction between α-AMA and GSTA1 was evaluated using molecular docking and Drug Affinity Responsive Target Stability (DARTS) assays. In vitro mechanisms were further dissected in HUH7 cells using siRNA knockdown, and functional rescue experiments. Results α-AMA caused significant liver injury, evidenced by elevated serum markers, worsened histopathology, and increased oxidative stress (reduced SOD/CAT, elevated MDA). Multi-omics analysis pinpointed GSTA1 and glutathione metabolism as central to the toxicity. Both molecular docking and DARTS assays confirmed a direct interaction between α-AMA and GSTA1. Mechanistically, α-AMA activated the NRF2 pathway, leading to upregulated GSTA1 expression. Paradoxically, GSTA1 silencing alleviated toxicity. This detrimental effect was mediated through GSTA1-driven depletion of cellular glutathione (GSH), resulting in reactive oxygen species (ROS) accumulation. Conclusion This study unveils a novel mechanism where α-AMA hijacks the NRF2-GSTA1 antioxidant axis, transforming GSTA1 from a detoxifier into a key perpetrator of hepatotoxicity via GSH depletion, ROS overproduction. GSTA1 emerges as a promising direct therapeutic target and potential diagnostic biomarker for α-AMA poisoning, highlighting a critical direction for future research.
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高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2023
·
IF 6.1
Yulin Zhao,Haoyan Huang,Ning Lv,Chunyan Huang,Huili Chen,Han Xing,Chaorui Guo,Ning Li,Di Zhao,Xijing Chen,Yongjie Zhang
Genipin (GP), the reactive metabolite of geniposide (GE), is responsible for GE-induced hepatotoxicity. As a potential detoxification pathway, the inactivation of GP by glutathione S-transferases (GSTs) has not yet been characterized. In this study, the thiol-GSH conjugates of GP, M532-1 and M532-2 were first identified and the catalytic activities of GSTs were investigated both in vitro and in vivo. GSTA1-1 and GSTA4-4 showed high activity in the formation of both thiol-GSH conjugates, whereas GSTA4-4 specifically catalyzed M532-2 formation in vitro. The active GST isoforms protect against alkylation of N-acetylcysteine (NAC), a classic model nucleophile. GST inhibition attenuated M532-1 formation in rat bile, confirming the in vivo catalytic role of GSTs. In conclusion, this study demonstrated the inactivation of GP by GSTs and implied that interindividual variability of GSTs may be a risk factor for susceptibility to GE-induced hepatotoxicity.
研究领域:
药理学
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毒理学
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生物化学
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高影响因子
JOURNAL OF APPLIED TOXICOLOGY
·
2019
·Vol. 39
·期 12
·1640-1650
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IF 3.065
Yicong Chang,Feng Wang,Yang Yang,Yuanyuan Zhang,Ishfaq Muhammad,Rui Li,Changwen Li,Ying Li,Chenxi Shi,Xin Ma,Beili Hao,Fangping Liu
Acetaminophen (APAP) is an antipyretic and analgesic, which is commonly associated with drug-induced hepatic injury. C2-ceramide plays a key role in mediating cell life activities, and oltipraz was extensively studied as a cancer chemopreventive agent. Glutathione S -transferase A1 (GSTA1) acts as a vital liver detoxification enzyme. Hepatocyte nuclear factor 1 (HNF-1) regulates various cellular signaling pathways. In this study, we investigated the effects of C2-ceramide and oltipraz on APAP-induced hepatocyte injury and the changes of HNF-1 and GSTA1. Results showed that C2-ceramide (6 μmol/L) exacerbated APAP-induced hepatocyte injury and caused a significant decrease ( P < .01) in HNF-1 and GSTA1 expressions. Meanwhile, GSTA1 content in supernatant was significantly increased ( P < .01). In contrast, oltipraz (8 μmol/L) reduced the injury and significantly elevated ( P < .01) HNF-1 and GSTA1 expressions while GSTA1 content in supernatant was significantly decreased ( P < .01). In conclusion, these findings revealed that C2-ceramide inhibited HNF-1 and GSTA1 expression and exacerbated hepatocyte injury, while oltipraz treatment results in the reduction of hepatocyte injury, and promoted HNF-1 and GSTA1 expression. Additionally, the changes in HNF-1 and GSTA1 were related to APAP-induced hepatocyte injury. These results were useful to investigate the mechanism of an antipyretic and analgesic drug combination.
研究领域:
药理学
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毒理学
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分子生物学
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高影响因子
JOURNAL OF APPLIED TOXICOLOGY
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2021
·Vol. 41
·期 12
·2011-2020
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IF 3.446
Yuanyuan Zhang,Bingke Ma,Shuangshuang Hao,Jiaqi Wang,Ruichen Zhang,Muhammad Ishfaq,Chenxi Shi,Liang Yuan,Rui Li,Changwen Li,Fangping Liu
Drug-induced liver injury (DILI) is a serious and frequently occurring issue in drug development. The c-Jun N-terminal kinase (JNK) signaling pathway plays an important role in many diseases; hepatocyte nuclear factor-1α (HNF-1α) and glutathione S-transferase A1 (GSTA1) are important in regulating liver-specific genes expressions and affecting drug metabolism. Oltipraz is used to treat liver cirrhosis by improving liver function, and C2-ceramide is a pro-apoptotic lipid that regulates multiple signaling pathways. In this study, we investigated the function of the JNK signaling pathway with HNF-1α and GSTA1 in a cellular model of DILI and whether oltipraz and C2-ceramide exert effects via the JNK pathway. The results showed that inhibiting JNK could ameliorate APAP-induced hepatocyte injury, reduced oxidative stress, suppressed JNK and c-Jun activation, and hepatocyte apoptosis. Meanwhile, the mRNA and protein expressions of HNF-1α and GSTA1 were increased significantly compared to control conditions. The effect of oltipraz (8 μmol/L) was similar to a JNK inhibitor and significantly increased HNF-1α/GSTA1 expression, but oltipraz combined with JNK inhibitor did not show a synergistic effect. Although C2-ceramide (8 μmol/L) aggravated hepatocyte injury and apoptosis, exacerbated oxidative stress, increased phosphorylation of JNK and c-Jun, and markedly decreased HNF-1α/GSTA1 expression, C2-ceramide combined with JNK inhibitor could partially alleviate these alterations. These results demonstrated that the JNK signaling pathway with HNF-1α/GSTA1 are involved in the process of DILI. Inhibiting JNK up-regulated HNF-1α and GSTA1 expressions which could attenuate hepatocyte injury. Oltipraz and C2-ceramide might affect the expression of HNF-1α/GSTA1 though JNK signaling.
研究领域:
药理学
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肝脏病学
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分子生物学
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DOI
PubMed
高影响因子
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