Metabolic insights into the hepatoprotective role of N-acetylcysteine in mouse liver.
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 1H- and 31P-NMR (nuclear magnetic resonance) spectroscopy. 13C-NMR-isotopomer analysis was used to measure [U-13C]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 micromol/g ww, whereas hypotaurine (HTau) concentrations increased from 0.05 +/- 0.02 to 9.95 +/- 1.12 micromol/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 13C-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. In conclusion, NAC (1) has a limited capacity to elevate GSH synthesis; (2) increases HTau formation linearly; and (3) improves mitochondrial tricarboxylic acid (TCA) cycle metabolism by stimulation of carbon flux through PDH. This latter effect is independent of the capacity of NAC to replete GSH stores. These metabolic actions, among other yet unknown effects, are critical for NAC's therapeutic value and should be taken into account when deciding on a wider use of NAC.
Centre de recherche, Centre hospitalier de l'Université de Montréal, Hôpital Saint-Luc, Montreal, Quebec, Canada. czwingmann@web.de
Claudia
C
Zwingmann
Marc
M
Bilodeau
D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D056486:Chemical and Drug Induced Liver Injury; D002952:Citric Acid Cycle / Q000187:drug effects / Q000502:physiology; D019610:Cytoprotection / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D005978:Glutathione / Q000096:biosynthesis; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D008107:Liver Diseases / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008930:Mitochondria, Liver / Q000378:metabolism; D009574:Nitro Compounds; D018384:Oxidative Stress; D011422:Propionates; D011766:Pyruvate Carboxylase / Q000378:metabolism; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism; D013654:Taurine / Q000031:analogs & derivatives / Q000096:biosynthesis; D020122:tert-Butylhydroperoxide
D000975:Antioxidants; D009574:Nitro Compounds; D011422:Propionates; D011768:Pyruvate Dehydrogenase Complex; D013654:Taurine; C003949:hypotaurine; D020122:tert-Butylhydroperoxide; D011766:Pyruvate Carboxylase; D005978:Glutathione; C015392:3-nitropropionic acid; D000111:Acetylcysteine