N-acetylcysteine induces shedding of selectins from liver and intestine during orthotopic liver transplantation

Abstract

SUMMARYIn orthotopic liver transplantation (OLT), N-acetylcysteine (NAC) reduces ischaemia/reperfusion (I/R) injury, improves liver synthesis function and prevents primary nonfunction of the graft. To further elucidate the mechanisms of these beneficial effects of NAC, we investigated influence of high-dose NAC therapy on the pattern of adhesion molecule release from liver and intestine during OLT. Nine patients receiving allograft OLT were treated with 150 mg NAC/kg during the first hour after reperfusion; 10 patients received the carrier only. One hour after reperfusion, samples of arterial, portal venous and hepatic venous plasma were taken and blood flow in the hepatic artery and the portal vein was measured. Absolute concentrations of sICAM-1, sVCAM-1, sP-selectin and sE-selectin were not markedly different. However, balance calculations showed release of selectins from NAC-treated livers as opposed to net uptake in controls (P # 0´02 for sP-selectin). This shedding of selectins might be a contributing factor to the decrease in leucocyte adherence and improved haemodynamics found experimentally with NAC-treatment.

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

“…27,28 Labeling of Metabolites with 13 C. [U- 13 C]glucose allows determination of metabolic pathways used to synthesize downstream compounds. [13][14][15][16][17]27 Briefly, via glycolysis, 1 molecule [U- 13 [1,2,[3][4][5][6][7][8][9][10][11][12][13] C]oxaloacetate, which condenses with acetyl-CoA into citrate. Glucose flux through these 2 pathways can be quantified from 13 C-NMR spectra from the 13 C-labeling pattern in glutamate (Glu) synthesized from the TCA cycle intermediate ␣-ketoglutarate.…”

“…After treatment with NAC, the relative de novo synthesis of GSH via PC (fractional enrichment in [2,3-13 C]GSH) decreased from 1.98% Ϯ 0.30% to 0.87% Ϯ 0.11% at a 300-mg/kg dose (P Ͻ .05; Fig. 4 [4,[5][6][7][8][9][10][11][12][13] C]Glu is a measure of carbon flux through PDH (Supplemental Fig. 1).…”

“…[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.…”

“…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.…”