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Interaction between arylating quinones and thiols - A proposed mechanism of quinones toxicity

Pasquet, Jean-Paul Edouard Emile; (1995) Interaction between arylating quinones and thiols - A proposed mechanism of quinones toxicity. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

It is a matter of controversy to attribute quinone toxicity to either covalent binding or redox cycling activity. Paracetamol with its putative reactive metabolite N-acetyl-p-benzoquinoneimine (NAPQI) is a classical example of this debate. It has been chosen together with para-benzoquinone (BQ), another possible reactive metabolite of paracetamol and a more stable quinone than NAPQI, to examine interaction of quinones with their main target, thiols. The initial step in the study has been to assess paracetamol toxicity in a rat liver slice system. The ability of different protecting agents to prevent paracetamol cytotoxicity was investigated and the relation between thiol (glutathione and thiol-protein) status and tissue injury were assessed. Depletion of glutathione (GSH) and oxidative processes but not quantitative loss of protein-SH seemed to relate to the injury. The second step of investigation was based on the idea that formation of quinone adducts to protein-SH could be necessary but not sufficient to lethally damage the cell. They could, however, if still redox active, trigger a long-lived generation of harmful radical species in the very vicinity of key proteins. p-Benzoquinone (BQ) was then shown, in a non-living system, to react with GSH to form HPLC-detectable conjugates which autoxidised to H2O2 at a rate which was more rapid than hydroquinone autoxidation. Different methyl-substituted BQs as well as 1,4-naphthoquinone and menadione reacted with GSH to form H2O2 to different extents, depending on their ability to deplete GSH. Synthesised NAPQI was shown to bind GSH and to form some H2O2 upon reaction with GSH. Glutathione, and other thiols, in large excess, were able to prevent or delay the autoxidation of hydroquinones. Similar reactions occurred when BQ was incubated with lens crystallins, the thiol-rich proteins of the lens. In this case, H2O2 production was associated with crystallin fragmentation, which seemed to be "site-specific" in terms of the specificity of protein fragment and susceptibility to inhibition by exogenous antioxidants. We propose that arylation and redox cycling could act together to form a mechanism responsible for cytotoxicity of quinones.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Interaction between arylating quinones and thiols - A proposed mechanism of quinones toxicity
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Pure sciences; Quinones
URI: https://discovery.ucl.ac.uk/id/eprint/10104248
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