Postabsorption antidotal effects of N-acetylcysteine on acetaminophen-induced hepatotoxicity in the mouse

Abstract

Male Swiss Webster mice, treated with N-acetylcysteine (NAC, 500 mg/kg po) 1 h following acetaminophen (NAPA, 350 mg/kg po) administration, had control levels of transaminases indicating that NAC protects against NAPA-induced hepatotoxicity by postabsorption antidotal mechanism(s). Hepatic congestion induced by NAPA was reduced by NAC. Significantly higher elimination rate constants (K) for indocyanine green (500 micrograms/kg, iv) in mice treated with NAPA and NAC (K = 0.676 +/- 0.062) than in animals receiving NAPA alone (0.341 +/- 0.105) suggested NAC improved or preserved the hepatic circulation of the compromised liver. This NAC-induced improvement and (or) preservation of hepatic circulation was reflected in biliary and urinary excretion of acetaminophen and its metabolites by a general increase in elimination during the first 6 h (70.2 +/- 2.6 vs. 32.6 +/- 7.1%), and in the repletion of glutathione (GSH) in the liver by a return to control levels more quickly (3 vs. greater than 5 h) following depletion by NAPA. The metabolic consequences of the postabsorption antidotal effect of NAC in the compromised liver was a preferential excretion of sulphydryl-derived metabolites in the 1-4 h bile (GSH conjugate 11.30 +/- 1.25 vs. 7.25 +/- 0.39%) which was subsequently observed in the urine by preferential excretion of glutathione degradation products.

Antioxidative and hepatoprotective effects of magnolol on acetaminophen-induced liver damage in rats

“…The characteristic zone 3 necrosis of APAP appears to be produced by an electrophilic metabolite of the drug NAPQI. NAPQI is initially detoxified by conjugation with reduced GSH to form mercapturic acid (Whitehouse et al, 1985). However, when the rate of NAPQI formation exceeds the rate of detoxication by GSH, NAPQI will oxidize tissue macromolecules, such as lipids or protein thiols, and alter the homeostasis of calcium after depleting GSH.…”

N-Acetylcysteine as an antioxidant and disulphide breaking agent: the reasons why

“…The resulting heavily cross-linked mucus is not easily transported and accumulates to cause airflow obstruction, atelectasis, and lung infection ( Figure 2) [24]. Pathologic mucus is typically highly elastic and thought to occur as a downstream consequence of airway inflammation [4]. NAC is a mucolytic agent able to reduce the heavy cross-linked mucus as already demonstrated in vitro by Sheffenr Figure 2.…”

“…In particular, the mucolytic action is due to the ability of NAC to break the disulphide bridges in the high-molecular-weight glycoproteins of mucus, resulting in reduced viscosity [3] ( Figure 1(b)). The effect of NAC on acetaminophen poisoning is a result of the action of NAC in replenishing hepatic reduced glutathione (GSH), which is the main endogenous nucleophilic peptide that reacts with and neutralises electrophilic and hence damaging molecules such as N-acetyl-p-benzoquinone imine (NAPQI), the electrophilic metabolite of acetaminophen [4] (Figure 1(c)). Since the 1980s, NAC has also been proposed for the treatment of diseases in which oxidative stress is considered to be involved in the onset and progression of the disease state [5].…”

Mechanism of the protective action of taurine in toxin and drug induced organ pathophysiology and diabetic complications: a review

“…146 NAPQI is mostly detoxified by conjugation with GSH to form mercapturic acid, leading to its depletion. 147 But in cases of APAP overdose, the rate of NAPQI formation exceeds the rate of its detoxification by GSH. As a result, NAPQI binds to cellular proteins and DNA and induces oxidative stress, leading to hepatic/renal injury and necrosis, although APAPinduced nephrotoxicity is less common than hepatotoxicity.…”