Molecular mechanisms of diketone neurotoxicity.
Chem-Biol Interact 1985 Aug; 54(3):257-270
Data concerning the neurotoxic mechanism of diketones such as n- hexane (110543), methyl-n-butyl-ketone (591786) (MNBK), and 2,5- hexanedione (110134) is reviewed. Neurotoxic diketones exhibit an organ specific toxicity, since only the nervous system and the testicular germinal epithelium appear to be affected. Only those compounds with a gamma diketone structure or those compounds which can be metabolized to a gamma diketone are capable of inducing a neurotoxic syndrome. A pathological sign of this neuropathy is axonal swelling due to the massive accumulation of 10 nanometer neurofilaments within the axoplasm of selected peripheral and central nervous system fibers. The distribution of this swelling appears to be dependent upon both the structural characteristics and dose of the gamma-diketone administered. MNBK and 2,5-hexanedione react covalently with tissue macromolecules in-vivo. Gamma diketones appear to act directly upon one or more axonal components, since neurofilament accumulation can be induced by the direct application of 2,5-hexanedione to nerve fibers, by intraneural injection, or by incorporation into the nutrient medium of nervous tissue culture systems. Mechanisms for the neurotoxicity of diketones proposed by various researchers to date include the induction of axonal glycolysis, the physicochemical alteration of neurofilaments, the inhibition of sterologenesis, decreased myelin membrane microviscosity, the specific inhibition of the calcium activated axonal proteases believed responsible for the normal degradation of neurofilament protein, the disruption of axonal membrane ion balance, the simultaneous reaction of gamma diketones with a sulfhydryl group of a thiamine dependent enzyme within an axon and with the amino group of thiamine itself, the chelation of mitochondrial calcium, and acetylcholinesterase inhibition. The author concludes that the actual mechanism of diketone neurotoxicity almost certainly involves the covalent interaction of 2,5- hexanedione with the lysine amine groups of neurofilaments or other axonal proteins.
NIOSH-Publication; NIOSH-Grant; Neurotoxic-effects; Molecular-structure; Solvents; Industrial-chemicals; Metabolic-study; Laboratory-animals; Toxic-effects; In-vivo-studies; Pathogenesis; Enzymes; Proteins
Biochem and Genetic Toxicology New York State Dept of Health Empire State Plaza Albany, N Y 12201
110-54-3; 591-78-6; 110-13-4
Neurotoxic Disorders; Neurotoxic-effects
New York State Dept of Health, New York, New York