1,2-diacetylbenzene, the neurotoxic metabolite of a chromogenic aromatic solvent, induces proximal axonopathy

Toxicol Appl Pharmacol. 2001 Dec 1;177(2):121-31. doi: 10.1006/taap.2001.9301.

Abstract

Several widely used aromatic hydrocarbon solvents reportedly induce blue-green discoloration of tissues and urine in animals and humans. The chomophore has been proposed to result from a ninhydrin-like reaction with amino groups in proteins. The present study examines the neurotoxic property of 1,2-diacetylbenzene (1,2-DAB), the active metabolite of the chromogenic and neurotoxic aromatic solvent 1,2-diethylbenzene. Rats treated with 1,2-DAB, but not with the nonchromogenic isomer 1,3-DAB or with ninhydrin developed blue discoloration of internal organs, including the brain and spinal cord. Only 1,2-DAB induced limb weakness associated with nerve fiber changes, which were most prominent in spinal cord and spinal roots. Changes began with the formation of proximal, neurofilament-filled axonal swellings of the type seen after treatment with 3,4-dimethyl-2,5-hexanedione, a potent derivative of the active metabolite of the neurotoxic aliphatic hydrocarbon solvents n-hexane and methyl n-butyl ketone. These compounds are metabolized to a gamma-diketone that forms pyrroles with target proteins, such as neurofilament proteins. A comparable mechanism is considered for 1,2-DAB, an aromatic gamma-diketone.

Publication types

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

MeSH terms

  • Acetophenones / toxicity*
  • Animals
  • Axons / drug effects*
  • Axons / pathology
  • Benzene Derivatives / toxicity
  • Brain / drug effects
  • Brain / pathology
  • Chromogenic Compounds / toxicity*
  • Indicators and Reagents / pharmacology
  • Male
  • Microscopy, Electron
  • Nervous System Diseases / chemically induced*
  • Nervous System Diseases / pathology
  • Ninhydrin / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Spinal Cord / drug effects
  • Spinal Cord / pathology
  • Structure-Activity Relationship

Substances

  • Acetophenones
  • Benzene Derivatives
  • Chromogenic Compounds
  • Indicators and Reagents
  • 1,2-diethylbenzene
  • 1,2-diacetylbenzene
  • Ninhydrin