Metabolic insights into the hepatoprotective role of N-acetylcysteine in mouse liver

Abstract

The hepatoprotective mechanisms of N-acetylcysteine (NAC) in non-acetaminophen-induced liver injury have not been studied in detail. We investigated the possibility that NAC could affect key pathways of hepatocellular metabolism with or without changes in glutathione (GSH) synthesis. Hepatocellular metabolites and high-energy phosphates were quantified from mouse liver extracts by 1 H-and 31 P-NMR (nuclear magnetic resonance) spectroscopy. 13 C-NMR-isotopomer analysis was used to measure [U-13 C]glucose metabolism through pyruvate dehydrogenase (PDH) and pyruvate carboxylase (PC). NAC (150-1,200 mg/kg) increased liver concentrations of GSH from 8.60 ؎ 0.48 to a maximum of 12.95 ؎ 1.03 mol/g ww, whereas hypotaurine (HTau) concentrations increased from 0.05 ؎ 0.02 to 9.95 ؎ 1.12 mol/g ww. The limited capacity of NAC to increase GSH synthesis was attributed to impaired glucose metabolism through PC. However, 300 mg/kg NAC significantly increased the fractional 13 C-enrichment in Glu (from 2.08% ؎ 0.26% to 4.00% ؎ 0.44%) synthesized through PDH, a key enzyme for mitochondrial energy metabolism. This effect could be uncoupled from GSH synthesis and was associated with the prevention of liver injury induced by tert-butylhydroperoxide and 3-nitropropionic acid. N -acetylcysteine (NAC) is the most widely administered antidote in acetaminophen intoxication. [1][2][3][4] In this setting, protection by NAC is believed to be attributable to its ability to regenerate glutathione (GSH) stores due to its capacity to provide cysteine (Cys) residues. However, NAC has also been shown to improve patient outcome after late administration, 5,6 pointing toward mechanisms independent from GSH replenishment. Furthermore, because NAC is recognized as an antioxidant, it might be useful in the setting of liver injuries different from those caused by acetaminophen intoxication. [6][7][8][9][10][11] NAC has also been reported to improve oxygen delivery, 4 to increase systemic oxygen consumption, 12 and to have beneficial effects on liver blood flow and function. 6,8,10 Because liver oxygen consumption is coupled with aerobic oxidation of energy substrates in the mitochondrial tricarboxylic acid (TCA) cycle, we hypothesize that NAC might improve hepatocellular energy metabolism. This effect might be salutary in the setting of nonacetaminophen-induced liver injury.We were particularly interested in investigating how NAC is involved in hepatocellular metabolic pathways and whether these changes are associated with modulation of GSH synthesis. The liver is unique in its metabolic activity and harbors many interrelated pathways. Apart

Protective Properties of 2-Acetylcyclopentanone in a Mouse Model of Acetaminophen Hepatotoxicity

“…Indeed, previous research has suggested that NAC does not scavenge NAPQI and therefore cannot prevent the initial phase. Rather, NAC hepatoprotection might involve an alternative mechanism that impacts the toxic phase, e.g., free radical trapping, increased GSH synthesis, or enhanced mitochondrial energy production (Lauterburg et al, 1983;Corcoran et al, 1985b;reviewed in De Flora et al, 2001;Zwingmann and Bilodeau, 2006;Saito et al, 2010). Our observation that i.p.…”

2-Acetylcyclopentanone, an Enolate-Forming 1,3-Dicarbonyl Compound, Is Cytoprotective in Warm Ischemia-Reperfusion Injury of Rat Liver

“…5), because the relatively low concentration of the active species (thiolate) would consequentially limit electrophile scavenging. In fact, there is evidence that NAC cytoprotection involves an indirect mechanism that is not based on electrophile scavenging, for example, increased GSH synthesis or mitochondrial bioenergetics (Zwingmann and Bilodeau, 2006;Jaeschke and Woolbright, 2012).…”

An Indole Derivative Protects Against Acetaminophen-Induced Liver Injury by Directly Binding to N-Acetyl-p-Benzoquinone Imine in Mice

“…NAC is a comparatively safe drug for APAP-induced liver injury (AILI) and is currently being used to treat acute viral hepatitis and other acute hepatic failures (10). However, some studies show that a prolonged treatment with a high dose of NAC (600 to 1200 mg/kg per day) interferes with the normal hepatic mitochondrial metabolic processes and impairs liver regeneration after AILI by interrupting nuclear factor (NF)-jB signal pathways (22,34,37). Although there have been numerous studies on the detailed mechanisms of action of the effect of NAC on APAP toxicity, a new generation of drugs with improved efficacy and decreased interruption of normal hepatic function should be developed.…”