Molecular mechanisms of diketone neurotoxicity.
Wadsworth Center for Laboratories and Research, New York State Department of Health, Albany, New York 1988 Feb; :1-4
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.
NIOSH-Author; NIOSH-Grant; Neurotoxic-effects; Neuropathology; Nervous-system-disorders; Metabolic-study; Protein-chemistry
Biochem and Genetic Toxicology New York State Dept of Health Empire State Plaza Albany, N Y 12201
Final Grant Report
NTIS Accession No.
Neurotoxic Disorders; Neurotoxic-effects;
Wadsworth Center for Laboratories and Research, New York State Department of Health, Albany, New York
New York State Dept of Health, New York, New York