Molecular mechanisms of diketone neurotoxicity.
The important industrial and commercial solvents n-hexane and methyl n-butyl ketone undergo metabolic conversion in experimental animals and man to the neurotoxic gamma-diketone 2,5-hexanedione. Several molecular mechanisms of action have been proposed to explain the pathogenesis of gamma-diketone neuropathy. Such a mechanism must account for the target organ specificity, neurofilament accumulation, structure/activity relationships, in vivo covalent binding, and apparent direct axonal toxicity encountered in this syndrome. It has been proposed that the gamma-diketones exert their effects by reaction with sulfhydryl moieties of energy-producing axonal glycolytic enzymes, with resultant disruption of axoplasmic transport. Others have suggested that reaction instead occurs with lysine moieties of axonal cytoskeletal proteins to form alkyl pyrrole adducts, leading to damaging physicochemical changes in these proteins. Additional hypotheses involve inhibition of axonal sterologenesis, alterations in nerve membrane properties, and reduced neurofilament proteolysis within the nerve terminal. Although a comprehensive mechanism of action for the gamma-diketones remains to be demonstrated, much progress has been made toward this goal. Ultimate success awaits elucidation of the interactions of the neurotoxic diketones with axonal components at the molecular level. Previous reviews have addressed the historical, pharmacokinetic, and neuropathological aspects of this neuropathy. The present critique will examine proposed molecular mechanisms for the gamma-diketones with regard to theoretical considerations and experimental evidence.
D000818:Animals; D001369:Axons / Q000187:drug effects / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D007382:Intermediate Filaments / Q000187:drug effects / Q000648:ultrastructure; D007659:Ketones / Q000633:toxicity*; D009410:Nerve Degeneration; D009474:Neurons / Q000187:drug effects*; D009498:Neurotoxins; D013261:Sterols / Q000096:biosynthesis; D013329:Structure-Activity Relationship
D007659:Ketones; D009498:Neurotoxins; D013261:Sterols