Abstract
In this study, acetaminophen (APAP)-induced acute liver injury mice model was used to investigate the effects of C2-ceramide and oltipraz on hepatocyte nuclear factor 1 (HNF-1) and glutathione S-transferase A1 (GSTA1). Notably, C2-ceramide caused alteration in mice serum transaminases and liver tissue indexes, and aggravated hepatic injury, while oltipraz alleviated hepatic injury. By screening, the optimal concentrations of C2-ceramide and oltipraz were confirmed to be 120 and 150 μmol/L, respectively. In histopathology, karyolysis and more necrotic cells and bleeding spots were appeared on administration of C2-ceramide, but only a small amount of inflammatory cells infiltration was seen after oltipraz treatment. In addition, RT-PCR and western blot results revealed that the mRNA and protein expression levels of HNF-1 and GSTA1 in liver were significantly decreased (p < 0.01) with the administration of 120 μmol/L C2-ceramide. Meanwhile, GSTA1 content in serum increased up to 1.27-fold. In contrast, 150 μmol/L oltipraz incorporation to APAP model mice resulted in obvious elevation (p < 0.01) in the mRNA and protein expression levels of HNF-1 and GSTA1 in liver, and serum GSTA1 content decreased up to 0.77-fold. In conclusion, C2-ceramide could down-regulate the expression of HNF-1 and GSTA1 which exacerbated hepatic injury, while oltipraz could up-regulate the expression of HNF-1 and GSTA1 which mitigated hepatic injury.
Highlights
Drug-induced liver injury (DILI) is associated with oxidative stress induced via the drug itself and/or its metabolites or the body’s allergic reaction to certain drugs (Kaplowitz, 2004)
Polyclonal antibodies of glutathione S-transferase A1 (GSTA1) and hepatocyte nuclear factor 1 (HNF-1) were bought from ABclonal Biotechnology Co., Ltd. (Boston, MA, United States)
Hepatocyte nuclear factor (HNF)-1 is highly expressed in liver (Bjorkhaug et al, 2005), FIGURE 1 | (A,B) Effects of different concentrations of C2-ceramide on aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities in APAP-induced hepatic injury. (C,D) Effects of different concentrations of oltipraz on AST and ALT activities in APAP-induced hepatic injury. (E,F) Effects of different concentrations of C2-ceramide and oltipraz on AST and ALT activities in normal mice
Summary
Drug-induced liver injury (DILI) is associated with oxidative stress induced via the drug itself and/or its metabolites or the body’s allergic reaction to certain drugs (Kaplowitz, 2004). Due to lack of specificity, it is not Abbreviations: ALT, alanine aminotransferase; APAP, N-acetyl-p-aminophenol/acetaminophen/paracetamol; AST, aspartate aminotransferase; C2, C2-ceramide; DILI, drug-induced liver injury; DMEM, dulbecco’s modified eagle medium; DMSO, dimethyl sulfoxide; GSH, glutathione; GSH-Px, glutathione peroxidase; GST, glutathione S-transferases; GSTA1, glutathione S-transferase A1; HNF-1, hepatocyte nuclear factor 1; MDA, malondialdehyde; NAPQI, N-acetyl-p-benzoquinone imine; OL, oltipraz; SOD, superoxide dismutase. Studies reported that drug induced hepatotoxicity and the injury mechanisms bewitch the interest of scientists due to the increasing number of incidence of liver damage (Ilavenil et al, 2016; Cheng et al, 2017; Kim et al, 2017). The acute liver injury model induced by acetaminophen (APAP) is used as the most typical DILI model in clinical trials. GSTA1 was identified as a more sensitive indicator than aminotransferases by using APAPinduced hepatic injury (Liu et al, 2014)
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