Molecular mechanism of hexane neuropathy: significant differences in pharmacokinetics between 2.3-, 2.4-, and 2.5-hexanedione.

Abstract

Hexane neuropathy is thought to be produced through the direct action of its metabolite, 2, 5-hexanedione (2, 5-HD), on nervous tissues. 7-Diketones in-cluding 2, 5-HD are reported to be neurotoxic, whereas α, β, and δ-diketones are reported to be not. Experiments were designed to investigate the specificity of the y-diketones in terms of pharmacokinetics. 2, 3-HD (a-diketone), 2, 4-HD (α-diketone), and 2, 5-HD (7-diketone) were tested in this study. Aqueous solutions containing 0.5% of each HD were administered to rats by gavage. HDs in blood, brain, and sciatic nerve were determined at specific intervals after gavage by the extraction method with chloroform or the direct injection method using gas chromatography-mass spectrometry.Examination of tissue distribution revealed that 2, 5-HD was not selectively re-tained by nervous tissues. However, 2, 5-HD had higher concentrations and much longer elimination times in both blood and nervous tissues than 2, 3-HD and 2, 4-HD. Therefore, for an identical dose, 2, 5-HD has a much larger effective dose (con-centration in tissue x time retained by tissue) than 2, 3-HD and 2, 4-HD. These results suggest that the specific neurotoxicity of the 7-diketones is due to their pharmackinetic specificity.