Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, ON K1N 6N5, Canada.
Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, ON K1N 6N5, Canada.
Cell Chem Biol. 2019 Nov 21;26(11):1594-1607.e7. doi: 10.1016/j.chembiol.2019.09.007. Epub 2019 Sep 26.
"Antioxidant activity" is an often invoked, but generally poorly characterized, molecular property. Several assays are available to determine antioxidant activity, the most popular of which is based upon the ability of a putative antioxidant to reduce 2,2-diphenyl-1-picrylhydrazyl. Here, we show that the results of this assay do not correlate with the potency of putative antioxidants as inhibitors of ferroptosis, the oxidative cell death modality associated with (phospho)lipid peroxidation. We subsequently describe our efforts to develop an approach that quantifies the reactivity of putative antioxidants with the (phospho)lipid peroxyl radicals that propagate (phospho)lipid peroxidation (dubbed FENIX [fluorescence-enabled inhibited autoxidation]). The results obtained with FENIX afford an excellent correlation with anti-ferroptotic potency, which facilitates mechanistic characterization of ferroptosis inhibitors, and reveals the importance of H-bonding interactions between antioxidant and phospholipid that underlie both the lackluster antioxidant activity of phenols under physiologically relevant conditions and the emergence of arylamines as inhibitors of choice.
"抗氧化活性"是一个经常被提及但通常描述不充分的分子性质。有几种测定方法可用于确定抗氧化活性，其中最流行的方法是基于假定抗氧化剂还原 2,2-二苯基-1-苦肼基的能力。在这里，我们表明该测定法的结果与假定抗氧化剂作为铁死亡抑制剂的效力不相关，铁死亡是与（磷酸）脂质过氧化相关的氧化细胞死亡方式。随后，我们描述了我们开发一种方法的努力，该方法定量测定假定抗氧化剂与（磷酸）脂质过氧自由基的反应性，而过氧自由基会引发（磷酸）脂质过氧化（称为 FENIX[荧光抑制自动氧化]）。使用 FENIX 获得的结果与抗铁死亡效力具有极好的相关性，这有助于铁死亡抑制剂的机制特征描述，并揭示了抗氧化剂和磷脂之间氢键相互作用的重要性，这种相互作用不仅是酚类在生理相关条件下抗氧化活性不佳的基础，也是芳胺类作为首选抑制剂出现的基础。
