Neuroprotein Targets of γ-Diketone Metabolites of Aliphatic and Aromatic Solvents That Induce Central–Peripheral Axonopathy

Abstract

Peripheral neuropathy associated with chronic occupational and deliberate overexposure to neurotoxic organic solvents results from axonal degeneration in the central and peripheral nervous system. Human and experimental studies show that axonopathy is triggered by the action of neuroprotein-reactive γ-diketone metabolites formed from exposure to certain aliphatic solvents ( n-hexane, 2-hexanone) and aromatic compounds (1,2-diethylbenzene, 1,2-4-triethylbenzene, 6-acetyl-1,1,4,4-tetramethyl-7-ethyl-1,2,3,4-tetralin). Neuroprotein susceptibility is related primarily to their differential content of lysine, the ∊-amino group of which is targeted by γ-diketones. Specific neuroprotein targets have been identified, and the sequence of molecular mechanisms leading to axonal pathology has been illuminated. While occupational n-hexane neuropathy continues to be reported, lessons learned from its experimental study may have relevance to other causes of peripheral neuropathy, including those associated with aging and diabetes mellitus.