Importance of glucose-6-phosphate Dehydrogenase Activity in Cell Death

Am J Physiol. 1999 May;276(5):C1121-31. doi: 10.1152/ajpcell.1999.276.5.C1121.

Abstract

The intracellular redox potential plays an important role in cell survival. The principal intracellular reductant NADPH is mainly produced by the pentose phosphate pathway by glucose-6-phosphate dehydrogenase (G6PDH), the rate-limiting enzyme, and by 6-phosphogluconate dehydrogenase. Considering the importance of NADPH, we hypothesized that G6PDH plays a critical role in cell death. Our results show that 1) G6PDH inhibitors potentiated H2O2-induced cell death; 2) overexpression of G6PDH increased resistance to H2O2-induced cell death; 3) serum deprivation, a stimulator of cell death, was associated with decreased G6PDH activity and resulted in elevated reactive oxygen species (ROS); 4) additions of substrates for G6PDH to serum-deprived cells almost completely abrogated the serum deprivation-induced rise in ROS; 5) consequences of G6PDH inhibition included a significant increase in apoptosis, loss of protein thiols, and degradation of G6PDH; and 6) G6PDH inhibition caused changes in mitogen-activated protein kinase phosphorylation that were similar to the changes seen with H2O2. We conclude that G6PDH plays a critical role in cell death by affecting the redox potential.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3T3 Cells
  • Animals
  • Apoptosis / drug effects
  • Blood
  • COS Cells
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Cell Death* / drug effects
  • Enzyme Inhibitors / pharmacology
  • Gene Expression
  • Glucosephosphate Dehydrogenase / antagonists & inhibitors
  • Glucosephosphate Dehydrogenase / genetics
  • Glucosephosphate Dehydrogenase / metabolism*
  • Hydrogen Peroxide / pharmacology
  • Mice
  • Mice, Inbred BALB C
  • Oxidation-Reduction
  • PC12 Cells
  • Phosphorylation
  • Rats
  • Reactive Oxygen Species / metabolism
  • Transfection

Substances

  • Enzyme Inhibitors
  • Reactive Oxygen Species
  • Hydrogen Peroxide
  • Glucosephosphate Dehydrogenase
  • Calcium-Calmodulin-Dependent Protein Kinases