N-Acetyl Cysteine Overdose Inducing Hepatic Steatosis and Systemic Inflammation in Both Propacetamol-Induced Hepatotoxic and Normal Mice.

Gunn-Guang Liou,Sue-Hong Wang,Chi-Ting Li,Ming-Shiun Tsai,Yi-Ju Lee,Cheng-Chi Hsieh,Pin-Hung Li

doi:10.3390/antiox10030442

Abstract

Acetaminophen (APAP) overdose induces acute liver damage and even death. The standard therapeutic dose of N-acetyl cysteine (NAC) cannot be applied to every patient, especially those with high-dose APAP poisoning. There is insufficient evidence to prove that increasing NAC dose can treat patients who failed in standard treatment. This study explores the toxicity of NAC overdose in both APAP poisoning and normal mice. Two inbred mouse strains with different sensitivities to propacetamol-induced hepatotoxicity (PIH) were treated with different NAC doses. NAC therapy decreased PIH by reducing lipid oxidation, protein nitration and inflammation, and increasing glutathione (GSH) levels and antioxidative enzyme activities. However, the therapeutic effects of NAC on PIH were dose-dependent from 125 (N125) to 275 mg/kg (N275). Elevated doses of NAC (400 and 800 mg/kg, N400 and N800) caused additional deaths in both propacetamol-treated and normal mice. N800 treatments significantly decreased hepatic GSH levels and induced inflammatory cytokines and hepatic microvesicular steatosis in both propacetamol-treated and normal mice. Furthermore, both N275 and N400 treatments decreased serum triglyceride (TG) and induced hepatic TG, whereas N800 treatment significantly increased interleukin-6, hepatic TG, and total cholesterol levels. In conclusion, NAC overdose induces hepatic and systemic inflammations and interferes with fatty acid metabolism.

Highlights

Acetaminophen (APAP) is one of the most commonly used antipyretic and analgesic drugs
Tumor necrosis factor (TNF)-α, interleukin (IL)-6, and C-C motif chemokine ligand 2 (CCL2) enzyme-linked immunosorbent assay (ELISA) kits were supplied by BD
In combination with our previous results, we suggest that higher doses of N-acetyl cysteine (NAC) (N400 and N800) effectively reduce propacetamolinduced hepatotoxicity and promote liver regeneration

Summary

Introduction

Acetaminophen (APAP) is one of the most commonly used antipyretic and analgesic drugs. APAP is safe and effective at normal therapeutic doses [1], but if used in excess can cause severe necrosis of liver cells [2] and even kidney damage [3]. Severe overdose of APAP can lead to death in humans and laboratory animals [2,4]. NAPQI normally combines with glutathione (GSH) in the liver to be excreted in the Antioxidants 2021, 10, 442. If there is an excessive intake of APAP, limited GSH is consumed, and the remaining NAPQI combines with proteins in the cytoplasm and mitochondria to cause lipid peroxidation. The covalent modifications of mitochondrial proteins cause mitochondrial permeability transition followed by mitochondrial dysfunction. The dramatic increase in oxidative stress, DNA fragmentation, and death of hepatocytes induce liver damage or failure [5]

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