NAD-dependent isocitrate dehydrogenase as a novel target of tributyltin in human embryonic carcinoma cells

Sci Rep. 2014 Aug 5;4:5952. doi: 10.1038/srep05952.

Abstract

Tributyltin (TBT) is known to cause developmental defects as endocrine disruptive chemicals (EDCs). At nanomoler concentrations, TBT actions were mediated by genomic pathways via PPAR/RXR. However, non-genomic target of TBT has not been elucidated. To investigate non-genomic TBT targets, we performed comprehensive metabolomic analyses using human embryonic carcinoma NT2/D1 cells. We found that 100 nM TBT reduced the amounts of α-ketoglutarate, succinate and malate. We further found that TBT decreased the activity of NAD-dependent isocitrate dehydrogenase (NAD-IDH), which catalyzes the conversion of isocitrate to α-ketoglutarate in the TCA cycle. In addition, TBT inhibited cell growth and enhanced neuronal differentiation through NAD-IDH inhibition. Furthermore, studies using bacterially expressed human NAD-IDH and in silico simulations suggest that TBT inhibits NAD-IDH due to a possible interaction. These results suggest that NAD-IDH is a novel non-genomic target of TBT at nanomolar levels. Thus, a metabolomic approach may provide new insights into the mechanism of EDC action.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Differentiation / drug effects
  • Cell Line, Tumor
  • Citric Acid Cycle / drug effects*
  • Embryo, Mammalian
  • Endocrine Disruptors / chemistry
  • Endocrine Disruptors / toxicity*
  • Environmental Pollutants / chemistry
  • Environmental Pollutants / toxicity*
  • Humans
  • Isocitrate Dehydrogenase / antagonists & inhibitors*
  • Isocitrate Dehydrogenase / metabolism
  • Isocitrates / antagonists & inhibitors
  • Isocitrates / metabolism
  • Ketoglutaric Acids / antagonists & inhibitors
  • Ketoglutaric Acids / metabolism
  • Malates / antagonists & inhibitors
  • Malates / metabolism
  • Male
  • Molecular Docking Simulation
  • Neurons / drug effects
  • Neurons / metabolism
  • Neurons / pathology
  • Succinic Acid / antagonists & inhibitors
  • Succinic Acid / metabolism
  • Testis / drug effects
  • Testis / metabolism
  • Testis / pathology
  • Trialkyltin Compounds / chemistry
  • Trialkyltin Compounds / toxicity*

Substances

  • Endocrine Disruptors
  • Environmental Pollutants
  • Isocitrates
  • Ketoglutaric Acids
  • Malates
  • Trialkyltin Compounds
  • tributyltin
  • malic acid
  • isocitric acid
  • Succinic Acid
  • Isocitrate Dehydrogenase