Molecular Mechanisms of Diketone Neurotoxicity

Details

• Personal Author:
  DeCaprio AP
• Description:
  Formation of the pyrrole adduct following either acute or chronic exposure of rats to 2,5-hexanedione (110134) (HD) was investigated. Physicochemical characterization of serum albumin and axonal cytoskeletal protein from HD treated animals was undertaken, and specific sites of lysine modification were elucidated. In-vivo protein binding of nonneurotoxic HD was characterized and the ability of 2,4-HD to influence the time course of 2,5-HD neuropathy by competitive binding was assessed. An examination was also made of in-vitro covalent protein amine binding of other neurofilamentous neurotoxins. Findings supported the hypothesis that pyrrole formation in neurofilament protein is a required step in gamma- diketone neuropathy. The rapid reorganization of the axonal cytoskeleton seen with direct application of 2,5-HD to nerve fibers may involve pyrrole formation but not crosslinking, that at high concentrations 2,5-HD appears able to react with previously formed pyrroles to form higher adducts, that the rate determining step of the reaction is attack of the enamine nitrogen upon the second carbonyl function to form the pyrrole, that in-vivo alterations may result in disruption of axonal cytoskeletal function, and that the related neurotoxins are also capable of covalently modifying lysine amino groups in protein while acrylamide may preferentially react with sulfhydryl moieties. [Description provided by NIOSH]
• Subjects:
  Energy Metabolism Nervous System Nervous System Diseases Occupational Health Safety
• Keywords:
  Metabolic-study Nervous-system-disorders Neuropathology Neurotoxic-effects NIOSH-Author NIOSH-Grant Protein-chemistry
• Series:
  Grant Final Reports
• Document Type:
  Text
• Funding:
  Grant
• Genre:
  Final Grant Report
• Place as Subject:
  New York ; OSHA Region 2
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  OEP - Office of Extramural Programs
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  1-4
• NIOSHTIC Number:
  nn:00182774
• NTIS Accession Number:
  PB89-129860
• Citation:
  Wadsworth Center for Laboratories and Research, New York State Department of Health, Albany, New York 1988 Feb; :1-4
• Contact Point Address:
  Biochem and Genetic Toxicology New York State Dept of Health Empire State Plaza Albany, N Y 12201
• CAS Registry Number:
  2,5-Hexanedione (CAS RN 110-13-4)
• Federal Fiscal Year:
  1988
• NORA Priority Area:
  Neurotoxic Disorders ; Neurotoxic Effects
• Performing Organization:
  New York State Dept of Health, New York, New York
• Peer Reviewed:
  False
• Start Date:
  19840501
• Source Full Name:
  Wadsworth Center for Laboratories and Research, New York State Department of Health, Albany, New York
• End Date:
  19871031
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:a2d2f4a43f17eefb23b7f87771ec4b1a4889c4fdc56ab109c9e5c81c352737a183a33e6d08fce0dc49f89cee7ebfe5fd7f53d0df70fa9e9cefadf60b71f87137
• Download URL:
  https://stacks.cdc.gov/view/cdc/217753/cdc_217753_DS1.pdf
• File Type:
  [PDF - 219.70 KB ]