Hepatotoxicity Induced by Isoniazid-Lipopolysaccharide through Endoplasmic Reticulum Stress, Autophagy, and Apoptosis Pathways in Zebrafish

Abstract

Isoniazid (INH) is a first-line antituberculosis drug. The incidence of adverse reactions accompanied by inflammation in the liver during drug administration to tuberculosis patients is high and severely affects clinical treatment. To better understand the mechanism of hepatotoxicity induced by INH under the inflammatory state, we compared the differences in levels of hepatotoxicity from INH between normal zebrafish and zebrafish in an inflammatory state to elucidate the hepatotoxic mechanism using different endpoints such as mortality, malformation, inflammatory effects, liver morphology, histological changes, transaminase analysis, and expression levels of certain genes. The results showed that the toxic effect of INH in zebrafish in an inflammatory state was more obvious than that in normal zebrafish, that liver size was significantly decreased as measured by liver fatty acid binding protein (LFABP) reporter fluorescence and intensity, and that alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were significantly increased. Hematoxylin and eosin (HE) staining and electron microscopy showed that hepatocyte injury was more obvious in the inflammatory state. In the inflammatory state, INH significantly increased the expression levels of endoplasmic reticulum stress (ERS)-related factors (GRP78, ATF6, PERK, IRE1, XBP1s, GRP94, and CHOP), autophagy-related factors (beclin 1, LC3, Atg3, and Atg12), and apoptosis-related factors (caspase-3, caspase-8, caspase-9, Bax, p53, and Cyt) in larvae. Correlational analyses indicated that the transcription levels of the inflammatory factors interleukin-1b (IL-1b), tumor necrosis factor beta (TNF-β), cyclooxygenase 2 (COX-2), and TNF-ɑ were strongly positively correlated with ALT and AST. Furthermore, the ERS inhibitor sodium 4-phenylbutyrate (4-PBA) could ameliorate the hepatotoxicity of INH-lipopolysaccharide (LPS) in zebrafish larvae. These results indicated that INH hepatotoxicity was enhanced in the inflammatory state. ERS and its mediated autophagy and apoptosis pathways might be involved in INH-induced liver injury promoted by inflammation.

Dihydromyricetin ameliorates chronic liver injury by reducing pyroptosis

“…Mature caspase-1 activates IL-1β. IL-1β, as the main inflammatory molecule of pyroptosis[ 38 ], is also one of the main factors that induces inflammation in CLI[ 38 - 40 ]. Therefore, IL-1β was selected as the inflammatory index observed.…”

Cantharidin‐induced LO2 cell autophagy and apoptosis via endoplasmic reticulum stress pathway in vitro

“…Furthermore, ERS can mediate autophagy and apoptosis based on unfolded protein response (UPR), calcium signaling, and tumor protein p53 (P53) signaling, and accumulation of unfolded or misfolded proteins in the ER leads to UPR, which are important in cellular self‐defense (Li et al, 2010; Qiu et al, 2019; Tian, Zeng, Li, Wu, & Wang, 2015; Wang, Chow, Chien, & Lin, 2018; Xi et al, 2015). These two processes have also been reported to play an important role in drug‐induced hepatotoxicity (Yongke & Arthur, 2015; Zhang et al, 2019). Studies have shown that CTD can induce tumor cell apoptosis and autophagy (Chen et al, 2011; Li et al, 2017; Liu, Li, Xu, Dai, & Chen, 2018; Ren et al, 2016); however, these effects have not been fully elucidated for normal cells.…”

Effective Combination of Isoniazid and Core-Shell Magnetic Nanoradiotherapy Against Gastrointestinal Tumor Cell Types

“…Fe 3 O 4 , MnO 2 , and INH induces cell apoptosis via the caspase mediated pathway, which involves caspase 3, 36 caspase 8, 37 and caspase 9. 38 Cell apoptosis in the NPs+INH+RT group was mediated by caspases 3, 8, and 9 through upregulated expression ( Figure S6 ). Moreover, Z-VAD-FMK, a caspase inhibitor was also applied to confirm the apoptosis pathway ( Figure S7 ).…”