GGsTop, a novel and specific γ-glutamyl transpeptidase inhibitor, protects hepatic ischemia-reperfusion injury in rats

Am J Physiol Gastrointest Liver Physiol. 2016 Aug 1;311(2):G305-12. doi: 10.1152/ajpgi.00439.2015. Epub 2016 Jun 30.

Abstract

Ischemia-reperfusion (IR) injury is a major clinical problem and is associated with numerous adverse effects. GGsTop [2-amino-4{[3-(carboxymethyl)phenyl](methyl)phosphono}butanoic acid] is a highly specific and irreversible γ-glutamyl transpeptidase (γ-GT) inhibitor. We studied the protective effects of GGsTop on IR-induced hepatic injury in rats. Ischemia was induced by clamping the portal vein and hepatic artery of left lateral and median lobes of the liver. Before clamping, saline (IR group) or saline containing 1 mg/kg body wt of GGsTop (IR-GGsTop group) was injected into the liver through the inferior vena cava. At 90 min of ischemia, blood flow was restored. Blood was collected before induction of ischemia and prior to restoration of blood flow and at 12, 24, and 48 h after reperfusion. All the animals were euthanized at 48 h after reperfusion and the livers were harvested. Serum levels of alanine transaminase, aspartate transaminase, and γ-GT were significantly lower after reperfusion in the IR-GGsTop group compared with the IR group. Massive hepatic necrosis was present in the IR group, while only few necroses were present in the IR-GGsTop group. Treatment with GGsTop increased hepatic GSH content, which was significantly reduced in the IR group. Furthermore, GGsTop prevented increase of hepatic γ-GT, malondialdehyde, 4-hydroxynonenal, and TNF-α while all these molecules significantly increased in the IR group. In conclusion, treatment with GGsTop increased glutathione levels and prevented formation of free radicals in the hepatic tissue that led to decreased IR-induced liver injury. GGsTop could be used as a pharmacological agent to prevent IR-induced liver injury and the related adverse events.

Keywords: 4-hydroxynonenal; GGsTop; TNF-α; ischemia; ischemia-reperfusion; γ-GT; γ-glutamyl transpeptidase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alanine Transaminase / blood
  • Aldehydes / metabolism
  • Aminobutyrates / pharmacology*
  • Animals
  • Aspartate Aminotransferases / blood
  • Cytoprotection
  • Disease Models, Animal
  • Enzyme Inhibitors / pharmacology*
  • Glutathione / metabolism
  • Interleukin-1beta / metabolism
  • Liver / drug effects*
  • Liver / enzymology
  • Liver / pathology
  • Liver Diseases / enzymology
  • Liver Diseases / pathology
  • Liver Diseases / prevention & control*
  • Male
  • Malondialdehyde / metabolism
  • Necrosis
  • Organophosphonates / pharmacology*
  • Oxidative Stress / drug effects
  • Rats, Wistar
  • Reperfusion Injury / enzymology
  • Reperfusion Injury / pathology
  • Reperfusion Injury / prevention & control*
  • Tumor Necrosis Factor-alpha / metabolism
  • gamma-Glutamyltransferase / antagonists & inhibitors*
  • gamma-Glutamyltransferase / blood

Substances

  • 2-amino-4-((3-(carboxymethyl)phenyl)(methyl)phosphono)butanoic acid
  • Aldehydes
  • Aminobutyrates
  • Enzyme Inhibitors
  • IL1B protein, rat
  • Interleukin-1beta
  • Organophosphonates
  • Tumor Necrosis Factor-alpha
  • Malondialdehyde
  • gamma-Glutamyltransferase
  • Aspartate Aminotransferases
  • Alanine Transaminase
  • Glutathione
  • 4-hydroxy-2-nonenal