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Augmented glutathione synthesis decreases acrolein toxicity.

Abstract
We have shown recently that acrolein is more strongly involved in cell damage than reactive oxygen species during brain infarction. Thus, we tried to isolate cells with reduced susceptibility to acrolein toxicity to clarify how acrolein is detoxified under cell culture conditions. The IC(50) of acrolein in mouse mammary carcinoma FM3A cells and in neuroblastoma Neuro2a cells was 2.6 and 4.2μM, respectively, but in acrolein toxicity-decreasing FM3A (FM3A-ATD) cells and Neuro2a (Neuro2a-ATD) cells, it was 7.6 and 8.4μM, respectively. In both FM3A-ATD and Neuro2a-ATD cells, the concentration of glutathione (GSH) was increased, so that detoxification occurred through acrolein conjugation with GSH. In FM3A-ATD cells, the level of a rate-limiting enzyme of GSH synthesis, γ-glutamylcysteine ligase catalytic unit (GCLC), was increased through the reactivation of one inactive allele of GCLC genes in FM3A cells. In Neuro2a-ATD cells, phosphorylation of transcription factors (c-Jun and NF-κB) necessary for expression of genes for GCLC and glutathione synthetase (GSHS) involved in GSH synthesis was stimulated, so that transcription of two genes increased in Neuro2a-ATD cells. Phosphorylation of JNK (c-Jun N-terminal kinase), which catalyzes phosphorylation of c-Jun and NF-κB p65, was also increased in Neuro2a-ATD cells, suggesting that activation of JNK kinase is responsible for the increase in GSH. These results support the idea that GSH plays important roles in detoxification of acrolein, because GSH is increased in both FM3A-ATD and Neuro2a-ATD cells.
AuthorsHideyuki Tomitori, Mizuho Nakamura, Akihiko Sakamoto, Yusuke Terui, Madoka Yoshida, Kazuei Igarashi, Keiko Kashiwagi
JournalBiochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 418 Issue 1 Pg. 110-5 (Feb 03 2012) ISSN: 1090-2104 [Electronic] United States
PMID22244891 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2012 Elsevier Inc. All rights reserved.
Chemical References
  • NF-kappa B
  • Acrolein
  • JNK Mitogen-Activated Protein Kinases
  • Glutamate-Cysteine Ligase
  • Glutathione
Topics
  • Acrolein (antagonists & inhibitors, metabolism, toxicity)
  • Animals
  • Base Sequence
  • Cell Culture Techniques
  • Cell Line, Tumor
  • Cell Separation
  • Exons
  • Gene Expression Regulation, Enzymologic
  • Glutamate-Cysteine Ligase (genetics)
  • Glutathione (biosynthesis)
  • Introns
  • JNK Mitogen-Activated Protein Kinases (metabolism)
  • Mice
  • Molecular Sequence Data
  • NF-kappa B (metabolism)
  • Oxidative Stress
  • Phosphorylation

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