Probing mechanisms of axonopathy. Part II: Protein targets of 2,5-hexanedione, the neurotoxic metabolite of the aliphatic solvent n-hexane

Toxicol Sci. 2009 Feb;107(2):482-9. doi: 10.1093/toxsci/kfn241. Epub 2008 Nov 25.


Neuroprotein changes in the spinal cord of rodents with aliphatic gamma-diketone axonopathy induced by 2,5-hexanedione (2,5-HD) are compared with those reported previously in aromatic gamma-diketone-like axonopathy induced by 1,2-diacetylbenzene (1,2-DAB). Sprague-Dawley rats were treated intraperitoneally with 500 mg/kg/day 2,5-HD, equimolar doses of 2,3-hexanedione (negative control), or an equivalent amount of saline containing 50% dimethyl sulfoxide (vehicle), 5 days a week, for 3 weeks. Analysis of the lumbosacral proteome by 2-dimensional differential in-gel electrophoresis and matrix-assisted laser desorption ionization time-of-flight/tandem mass spectrometry revealed 34 proteins markedly modified by 2,5-HD of which neurofilament triplet L, gelsolin, protein disulfide isomerase, glutathione S-transferase, nicotinamide adenine dinucleotide (reduced) dehydrogenase 1 alpha, pyruvate kinase, and fatty acid synthase were also modified by 1,2-DAB. The expression of proteins involved in maintaining the physical integrity of the cytoskeleton or controlling the redox and protein-folding mechanisms was reduced, whereas that of proteins supporting energy metabolism was mainly increased. The similarity of the neuroproteomic patterns of 2,5-HD and 1,2-DAB axonopathy suggests common biomarkers and/or mechanisms of neurotoxicity associated with exposure to their parent chemicals, namely the industrial solvents n-hexane and 1,2-diethylbenzene, respectively.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetophenones / toxicity
  • Amino Acids / metabolism
  • Animals
  • Axons / pathology*
  • Biomarkers
  • Cell Shape / drug effects
  • Electrophoresis, Polyacrylamide Gel
  • Hexanes / pharmacokinetics
  • Hexanes / toxicity*
  • Hexanones / toxicity*
  • Isoelectric Focusing
  • Male
  • Nerve Tissue Proteins / drug effects*
  • Neurofilament Proteins / metabolism
  • Neurotoxicity Syndromes / pathology*
  • Neurotoxins / toxicity*
  • Proteomics
  • Rats
  • Rats, Sprague-Dawley
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
  • Spinal Cord / drug effects
  • Spinal Cord / metabolism
  • Spinal Cord / pathology


  • Acetophenones
  • Amino Acids
  • Biomarkers
  • Hexanes
  • Hexanones
  • Nerve Tissue Proteins
  • Neurofilament Proteins
  • Neurotoxins
  • n-hexane
  • 1,2-diacetylbenzene
  • 2,5-hexanedione