Divergent effects of glutathione depletion on isocitrate dehydrogenase 1 and the pentose phosphate pathway in hamster liver

Research output: Contribution to journalArticle

Abstract

The liver regenerates NADPH via multiple pathways to maintain redox balance and reductive biosynthesis. The pentose phosphate pathway (PPP) contributes to hepatic lipogenesis by supplying NADPH, and it is thought to play a major role in response to oxidative stress. This study determined the significance of the PPP and related NADPH-regenerating enzymes in the liver under oxidative stress. Fasted hamsters received acetaminophen (400 mg/kg) to deplete glutathione in the liver and [U-13C3]glycerol to measure the PPP activity by analysis of 13C distribution in plasma glucose. Blood and liver were harvested to assess NADPH-producing enzymes, antioxidant defense, PPP, and other relevant biochemical processes. Acetaminophen caused glutathione depletion and decreased activities of glutathione peroxidase and catalase in the liver, but it did not change triglyceride synthesis. Although the PPP is potentially an abundant source of NADPH, its activity was decreased and the expression of glucose 6-phosphate dehydrogenase remained unchanged after acetaminophen treatment. The effects of acetaminophen on other NADPH-producing enzymes were complex. Isocitrate dehydrogenase 1 was overexpressed, both isocitrate dehydrogenase 2 and malic enzyme 1 were underexpressed, and methylenetetrahydrofolate dehydrogenase 1 remained unchanged. In summary, isocitrate dehydrogenase 1 was most sensitive to glutathione depletion caused by acetaminophen, but glucose 6-phosphate dehydrogenase, the regulatory enzyme of PPP, was not.

Original languageEnglish (US)
Article numbere14554
JournalPhysiological Reports
Volume8
Issue number16
DOIs
StatePublished - Aug 1 2020

Keywords

  • NADPH-producing enzyme
  • acetaminophen
  • antioxidant activity
  • glycerol
  • mitochondria

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

Fingerprint Dive into the research topics of 'Divergent effects of glutathione depletion on isocitrate dehydrogenase 1 and the pentose phosphate pathway in hamster liver'. Together they form a unique fingerprint.

  • Cite this