当前位置： SCI文献检索 > CHEMICAL RESEARCH IN TOXICOLOGY期刊下所有文献 > Inhibition of 2,5-hexanedione-induced protein cross-linking by biological thiols: chemical mechanisms and toxicological implications.

Inhibition of 2,5-hexanedione-induced protein cross-linking by biological thiols: chemical mechanisms and toxicological implications.

Abstract：

:n-Hexane is metabolized to the gamma-diketone 2,5-hexanedione (2,5-HD), a derivative that covalently binds to lysine residues in neurofilament (NF) protein to yield 2,5-dimethylpyrrole adducts. Studies comparing the pyrrole-forming potential and neurotoxic potency of gamma-diketones have demonstrated that pyrrolylation is an absolute requirement in the neuropathogenesis. Autoxidative cross-linking of pyrrolylated NF proteins occurs and is proposed as a second required event. In the present study, the role of nucleophilic thiols and amines in the pyrrole-mediated cross-linking reaction was investigated. When pyrrolylated ribonuclease was incubated with N-acetyllysine, N-acetylcysteine, or glutathione in physiologic buffer (pH 7.4) under air, pyrrole-to-pyrrole cross-linking was inhibited only by the thiol-containing compounds. Stable thiol--pyrrole conjugates containing a bridge from the pyrrole ring at C-3 to the sulfur atom of the thiol were characterized by thermospray LC/MS and 1H-NMR spectroscopy. In contrast to low-molecular-mass thiols, SDS--PAGE studies indicated that, under the same incubation conditions, free thiols present in proteins did not undergo reaction with pyrrole adducts to form cross-links. Further experiments using a low-molecular-mass pyrrole derivative indicated that glutathione may also able to suppress pyrrole dimerization without conjugate formation, possibly via inhibition of a free radical-dependent mechanism. The results suggest the following: (1) 2,5-HD-induced protein cross-linking is mediated primarily by pyrrole-to-pyrrole bridging under physiologic conditions, and (2) glutathione and other low-molecular-mass thiols may inhibit the pyrrole dimerization reaction by two distinct pathways. These findings have significant implications for the mechanism of gamma-diketone neuropathy.

journal_name

Chem Res Toxicol

journal_title

Chemical research in toxicology

authors

Zhu M,Spink DC,Yan B,Bank S,DeCaprio AP

doi

10.1021/tx00047a017

subject

Has Abstract

pub_date

1995-07-01 00:00:00

pages

764-71

issue

eissn

0893-228X

issn

1520-5010

journal_volume

pub_type

杂志文章

在线工具

Inhibition of 2,5-hexanedione-induced protein cross-linking by biological thiols: chemical mechanisms and toxicological implications.