Glutamine Preserves Liver Glutathione After Lethal Hepatic Injury

Hong, Roy W.; Rounds, Jan D.; Helton, W. Scott; Robinson, Malcolm K.; Wilmore, Douglas W.

doi:10.1097/00000658-199202000-00004

Cited by 240 publications

(113 citation statements)

References 20 publications

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“…Our observation therefore supports a previous report demonstrating that Gln is also rate-limiting for GSH replenishment. 37,38 Another striking result was that NAC increased flux through PDH, which is important for mitochondrial energy metabolism through its ability to provide acetyl-CoA for the mitochondrial TCA cycle (Supplemental Fig. 1).…”

Section: Discussionmentioning

confidence: 99%

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

Zwingmann

Bilodeau

2006

Hepatology

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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

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Section: Discussionmentioning

confidence: 99%

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

Zwingmann

Bilodeau

2006

Hepatology

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“…Hypoxia may increase the hepatic uptake of glutamine which is a precursor for the production of the antioxidant glutathione (Hong et al 1992). Hypoxia is associated with an increased production of free radicals (Simon-Schnass 1994; Vasankari et al 1997) and thus the production of e ective free radical scavengers would prove bene®cial.…”

Section: Discussionmentioning

confidence: 99%

Implications of moderate altitude training for sea-level endurance in elite distance runners

Bailey

Davies

Romer

et al. 1998

European Journal of Applied Physiology

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Elite distance runners participated in one of two studies designed to investigate the e ects of moderate altitude training (inspiratory partial pressure of oxygen »115±125 mmHg) on submaximal, maximal and supramaximal exercise performance following return to sea-level. Study 1 (New Mexico, USA) involved 14 subjects who were assigned to a 4-week altitude training camp (1500±2000 m) whilst 9 performance-matched subjects continued with an identical training programme at sea-level (CON). Ten EXP subjects who trained at 1640 m and 19 CON subjects also participated in study 2 (Krugersdorp, South Africa). Selected metabolic and cardiorespiratory parameters were determined with the subjects at rest and during exercise 21 days prior to (PRE) and 10 and 20 days following their return to sealevel (POST). Whole blood lactate decreased by 23% (P < 0.05 vs PRE) during submaximal exercise in the EXP group only after 20 days at sea-level (study 1). However, the lactate threshold and other measures of running economy remained unchanged. Similarly, supramaximal performance during a standardised track session did not change. Study 2 demonstrated that hypoxia per se did not alter performance. In contrast, in the EXP group supramaximal running velocity decreased by 2% (P < 0.05) after 20 days at sea-level.Both studies were characterised by a 50% increase in the frequency of upper respiratory and gastrointestinal tract infections during the altitude sojourns, and two male subjects were diagnosed with infectious mononucleosis following their return to sea-level (study 1). Group mean plasma glutamine concentrations at rest decreased by 19% or 143 (74) lM (P < 0.001) after 3 weeks at altitude, which may have been implicated in the increased incidence of infectious illness.

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“…16 Two patients with VOD were treated using l-glutamine (in dipeptide form) plus vitamin E. 17 Although VOD resolved in both patients, the role of l-glutamine is difficult to determine. One of the patients had late-onset VOD, which is not considered in the above model.…”

Section: Glutathionementioning

confidence: 99%

Avoiding hepatic veno-occlusive disease: what do we know and where are we going?

Bearman

2001

Bone Marrow Transplant

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Summary:Hepatic venocclusive disease (V0D) is a common toxicity associated with myeloablative chemotherapy or chemoradiotherapy used to prepare patients for stem cell transplantation. A sizable proportion of patients who develop VOD die. It is clear that injury to endothelial cells and hepatocytes in zone 3 of the liver acinus is the initial event in the pathogenesis of VOD. What are less clear are the mechanisms of injury and whether this knowledge can be exploited. This manuscript will briefly review some recent data and discuss how that information has influenced clinical practice. Bone Marrow Transplantation (2001) 27, 1113-1120. Keywords: veno-occlusive disease; stem cell transplantation; toxicity VOD is characterized by a syndrome of jaundice, fluid retention and painful hepatomegaly and occurs in up to half of patients who receive ablative preparative therapy. 1 As many as half of patients with VOD die, usually of multiorgan failure. Signs of VOD usually present around the day of transplant, 2 although well described 'late onset VOD' has been reported. 3,4 Fluid retention and hepatomegaly are usually the first manifestations and typically present on or around the day of transplant. Jaundice develops later, around day 6. 2 The rate of rise in bilirubin and weight is also faster for patients whose illness is likely to be severe vs those who are likely to have self-limited disease. Furthermore, fewer than 20% of patients with mild VOD and 48% with severe VOD develop ascites. 2 These observations led to the development of a model p ϭ 1/(1 ϩ e Ϫz ) which would predict which patients with VOD were likely to die. 5 In this model, z ϭ ␤ 0 ϩ ␤ 1 (in total serum bilirubin) ϩ ␤ 2 (percent weight gain). The intercepts ␤ 0 , ␤ 1 and ␤ 2 change as day relative to transplant increases. 5 For

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Glutamine Preserves Liver Glutathione After Lethal Hepatic Injury

Cited by 240 publications

References 20 publications

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

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

Implications of moderate altitude training for sea-level endurance in elite distance runners

Avoiding hepatic veno-occlusive disease: what do we know and where are we going?

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