Drug‐induced liver injury: Oltipraz and C2‐ceramide intervene HNF‐1α/GSTA1 expression via JNK signaling pathway

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 l...

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Published in:Journal of applied toxicology 2021-12, Vol.41 (12), p.2011-2020
Main Authors: Zhang, Yuanyuan, Ma, Bingke, Hao, Shuangshuang, Wang, Jiaqi, Zhang, Ruichen, Ishfaq, Muhammad, Shi, Chenxi, Yuan, Liang, Li, Rui, Li, Changwen, Liu, Fangping
Format: Article
Language:English
Subjects:
Apoptosis
C2‐ceramide
Ceramide
Chemical and Drug Induced Liver Injury - drug therapy
Cirrhosis
Drug development
Drug metabolism
drug‐induced liver injury
Glutathione
Glutathione Transferase - genetics
Glutathione Transferase - metabolism
GSTA1
Hep G2 Cells
Hepatocyte Nuclear Factor 1-alpha - genetics
Hepatocyte Nuclear Factor 1-alpha - metabolism
HNF‐1α
Humans
Injury prevention
JNK protein
JNK signaling pathway
Kinases
Lipids
Liver
Liver cirrhosis
MAP Kinase Signaling System
mRNA
Oltipraz
Oxidative stress
Phosphorylation
Pyrazines - pharmacology
Signal transduction
Signaling
Sphingosine - analogs & derivatives
Sphingosine - pharmacology
Synergistic effect
Thiones - pharmacology
Thiophenes - pharmacology
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Summary: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. Drug‐induced liver injury (DILI) is a major issue in the drug development. JNK signaling pathway plays a crucial role in many diseases and HNF‐1α/GSTA1 is important in regulating liver‐specific genes expressions or affecting drug metabolism. Results revealed that oltipraz (8 μmol/L) or C2‐ceramide (8 μmol/L) interfered JNK activation and HNF‐1α/GSTA1 expression, which are all involved in the process of DILI. Inhibiting JNK up‐regulated HNF‐1α and GSTA1, attenuated hepatocyte injury. Oltipraz and C2‐ceramide might affect HNF‐1α/GSTA1 expression via JNK signaling.
ISSN:0260-437X
1099-1263
DOI:10.1002/jat.4181