Potentiating effect of acetaminophen and carbon tetrachloride-induced hepatotoxicity is mediated by activation of receptor interaction protein in mice

Abstract

When multiple drugs or chemicals are used in combination, it is important to understand the risk of their interactions and predict potential additive effects. The aim of the current study was to investigate the molecular mechanism(s) accounting for the additive/synergistic effect of combination treatment with acetaminophen (APAP) and carbon tetrachloride (CCl). Mice were intraperitoneally administered vehicle or 100 mg/kg (5 mL/kg) APAP and 30 min after vehicle or 15 mg/kg (5 mL/kg) CCl. Sixteen hours after treatment, mice from each group were sacrificed and the livers were removed. CCl administration caused slight glycogen depletion; this effect was more pronounced following co-administration of APAP and CCl. ATP and NADPH levels showed the same trend as glycogen levels. The levels of receptor interacting protein 1 and 3 increased following combination treatment with APAP and CCl. In contrast, levels of the glutamate cysteine ligase catalytic subunit and glutamate cysteine ligase modifier subunits were not significantly affected by combination treatment. APAP and CCl co-administration potentiated the phosphorylation of c-Jun N-terminal kinase and p38 kinases, although phosphorylated activation of extracellular signal-regulated kinase was not changed. Our results suggest that APAP and CCl co-administration potentiates hepatotoxicity in an additive/synergistic manner via receptor interacting protein activation.

Different Renal Chronotoxicity of Bromobenzene and Its Intermediate Metabolites in Mice

“…8) We previously reported that streptomycin, which shows nephrotoxicity, was highly toxic following dark-phase exposure and less toxic following light-phase exposure. 9) These findings of the previous studies do not contradict with those of the present study, suggesting that differences in the toxicity of BB and the three BB intermediate metabolites are attributed to their target organs. BB targets the liver, whereas its intermediate metabolites target the kidneys.…”

“…In this study, we targeted "chronotoxicology" as we have previously suggested the relationship between the administration timing and the toxicity severity of chemicals. [7][8][9] Our previous study demonstrated notable daily fluctuations in the severity of toxic responses to BB in mice, i.e., mice were more tolerant to BB-induced hepatic injury during the dark-phase exposure (2:00) than during the light-phase exposure (14:00). 8) Although BB showed mild nephrotoxicity, chronotoxicity was not observed in the kidneys.…”

“…In our previous study, streptomycin, an antibiotic known to induce defined nephrotoxicity, showed clear diurnal variation in the induced nephrotoxicity in mice. 9) Based on the data available, we hypothesized that the chronotoxicity caused by BB is prominent in the liver rather than in the kidneys, thus masking the chronotoxicity in the latter organ. The metabolites of BB generated through various metabolic pathways occur in low concentrations and thus might contribute to negligible renal damage; owing to this, BB metabolite-induced nephrotoxicity cannot be estimated clinically.…”

Emodin Attenuates Acetaminophen-Induced Hepatotoxicity via the cGAS-STING Pathway

“…Oxidative stress is one of landmark events of APAP-induced acute hepatic injury [32]. In experiments of rodent model, routine dose of APAP were mainly involved in glucuronidation and sulfation, and the nontoxic metabolites were then excreted through vile and urine [33,34]. However, when excessive APAP is oxidated to NAPQI by cytochrome P450 (CYP), which binds with GSH to inhibit toxic responses [35,36].…”

Sasa veitchii extract protects against carbon tetrachloride-induced hepatic fibrosis in mice

“…Protein samples (30 μg) were subjected to gradient sodium dodecyl sulfate-polyacrylamide gel electrophoresis (BioRad, Hercules, CA, USA) and transferred to a polyvinylidene difluoride membrane using Trans-Blot Turbo Transfer System (BioRad). Next, the membrane was incubated with mouse anti-α-smooth muscle actin (anti-αSMA) monoclonal antibody (Santa Cruz), mouse anti-β-actin monoclonal antibody (MBL, Aichi, Japan), rabbit anti-c-Jun N-terminal kinase (JNK) polyclonal antibody, rabbit anti-phospho-JNK monoclonal antibody, rabbit-anti extracellular signal-regulated kinase (ERK) 1/2 monoclonal antibody, rabbit anti-phospho-ERK1/2 monoclonal antibody, rabbit-anti p38 monoclonal antibody, rabbit anti-phospho-p38 monoclonal antibody, peroxidase-conjugated anti-rabbit IgG (Cell Signaling Technology, Beverly, MA, USA), and peroxidase-conjugated anti-mouse IgG (BioRad) using previously described conditions [ 29 ]. Immuno-reactive bands were visualized with an ECL system (BioRad).…”