Structural basis of gamma-diketone neurotoxicity: non-neurotoxicity of 3,3-dimethyl-2,5-hexanedione, a gamma-diketone incapable of pyrrole formation.

The chronic exposure to gamma-diketones results in the formation of giant neurofilament (NF)-containing axonal enlargements, followed by axonal degeneration in peripheral axons. Based on the specific ability of gamma-diketones to react with primary amino groups to form pyrroles, and the observation of such reaction with NF protein in vitro and with other proteins in vivo, it has been proposed that pyrrole formation at primary amino groups of NF protein is responsible for the neurotoxicity of gamma-diketones. We have tested this hypothesis through an investigation of the neurotoxicity in rats of 3,3-dimethyl-2,5-hexanedione (3,3-DMHD), a gamma-diketone which is incapable of forming pyrroles. 3,3-DMHD was found to produce only a slight alteration of axonal caliber and no clinical neurotoxicity after up to 12 weeks of administration, at a dose over 20 times that for which its isomer 3,4-dimethyl-2,5-hexanedione (3,4-DMHD) produced massive focal NF-containing axonal enlargements and complete paralysis in 4 weeks. These results support the view that the pyrrole-forming capability of gamma-diketones is the initial molecular event in the pathogenesis of gamma-diketone neurotoxicity.