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

Abstract

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.

• Authors: Yuanyuan Zhang, Bingke Ma, Shuangshuang Hao, Jiaqi Wang, Ruichen Zhang, Muhammad Ishfaq, Chenxi Shi, Liang Yuan, Rui Li, Changwen Li, Fangping Liu
• Journal: Journal of applied toxicology : JAT (J Appl Toxicol) Vol. 41 Issue 12 Pg. 2011-2020 (12 2021) ISSN: 1099-1263 [Electronic] England
• PMID: 33959992 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 John Wiley & Sons, Ltd.

Chemical References

• Hepatocyte Nuclear Factor 1-alpha
• N-acetylsphingosine
• Pyrazines
• Thiones
• Thiophenes
• oltipraz
• GSTA1 protein, human
• Glutathione Transferase
• Sphingosine

Topics

• Chemical and Drug Induced Liver Injury (drug therapy)
• Glutathione Transferase (genetics, metabolism)
• Hep G2 Cells
• Hepatocyte Nuclear Factor 1-alpha (genetics, metabolism)
• Humans
• MAP Kinase Signaling System
• Pyrazines (pharmacology)
• Sphingosine (analogs & derivatives, pharmacology)
• Thiones (pharmacology)
• Thiophenes (pharmacology)