Studies of the molecular pathogenesis of hexane neuropathy: II. Evidence that pyrrole derivatization of lysyl residues leads to protein crosslinking,☆☆

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Abstract

In the reaction between ethanolamine and 2,5-hexanedione, 1-(2-hydroxyethyl)-2,5-dimethylpyrrole was formed, and the pyrrole was found to autoxidize to form an orange chromophore. Similar orange chromophores were observed in the reaction of 2,5-hexanedione, 2,5-heptanedione, and 3,6-octanedione with a variety of primary amines and with proteins. The development of the orange chromophore in the reaction of 2,5-hexanedione with proteins was attended by a proportional derivatization of lysyl residues and by extensive intramolecular and intermolecular crosslinking. These observations suggest that the sequence of events in the crosslinking of neurofilaments during chronic n-hexane intoxication may be metabolism to 2,5-hexanedione, formation of an imine with lysyl residues, cyclization to form a pyrrole, autoxidation of the pyrrole, and finally covalent crosslinking involving pyrrole rings.

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    This work was supported in part by NIEHS grant ESO2611-01.

    ☆☆

    Portions of this work were presented at the meetings of the Society of Toxicology, Washington, D.C., March 9–13, 1980, and of the American Association of Neuropathologists, New Orleans, La., June 13–15, 1980.

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