Pyrrole oxidation and protein cross-linking as necessary steps in the development of gamma-diketone neuropathy.

Published

Journal Article

It has been well documented that the gamma-diketone HD1 is the ultimate toxic metabolite of n-hexane. Furthermore, it has been shown that the pathogenetic mechanism by which HD exerts its neurotoxic effects is through binding to protein lysly residues and cyclization to pyrroles. The present study sought to determine whether the presence of pyrrole residues on NF1 proteins is sufficient to cause the NF-filled axonal swellings associated with n-hexane and other gamma-diketone neuropathies or whether pyrrole oxidation and protein cross-linking also have to occur in order for neurotoxicity to develop. We synthesized the HD analogue AcHD1 and assessed its rate of pyrrole formation in vitro, the ease of oxidation of its resulting pyrroles, and its ability to cross-link proteins in vitro. The in vivo effects of AcHD on rats were examined following daily ip1 injections. AcHD was found to have a rate of pyrrole formation comparable to that of the potent HD analogue DMHD1 at 35 degrees C. The pyrrole derived from AcHD was more resistant to oxidation than that derived from the neurotoxic compound HD. AcHD did not cross-link proteins in vitro. Pyrrole derivatives were demonstrated on hemoglobin isolated from animals treated with HD, DMHD, and AcHD. Cross-linked spectrin was detected in animals treated with HD and DMHD but not with AcHD. Rats receiving 0.1 or 0.25 mmol of AcHD/kg/day did not reach the end point of hindlimb paralysis observed in the gamma-diketone neuropathies, and the NF-filled axonal swellings seen following exposure to the neurotoxic gamma-diketones were not observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Full Text

Duke Authors

Cited Authors

  • Genter St Clair, MB; Amarnath, V; Moody, MA; Anthony, DC; Anderson, CW; Graham, DG

Published Date

  • May 1988

Published In

Volume / Issue

  • 1 / 3

Start / End Page

  • 179 - 185

PubMed ID

  • 2979729

Pubmed Central ID

  • 2979729

International Standard Serial Number (ISSN)

  • 0893-228X

Digital Object Identifier (DOI)

  • 10.1021/tx00003a009

Language

  • eng

Conference Location

  • United States