학술논문
Vitamin E hydroquinone is an endogenous regulator of ferroptosis via redox control of 15-lipoxygenase.
Document Type
Article
Author
Hinman, Andrew; Holst, Charles R.; Latham, Joey C.; Bruegger, Joel J.; Ulas, Gözde; McCusker, Kevin P.; Amagata, Akiko; Davis, Dana; Hoff, Kevin G.; Kahn-Kirby, Amanda H.; Kim, Virna; Kosaka, Yuko; Lee, Edgar; Malone, Stephanie A.; Mei, Janet J.; Richards, Steve James; Rivera, Veronica; Miller, Guy; Trimmer, Jeffrey K.; Shrader, William D.
Source
Subject
*VITAMIN E
*HYDROQUINONE
*LIPOXYGENASES
*NEURODEGENERATION
*CELL death
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Language
ISSN
1932-6203
Abstract
Ferroptosis is a form of programmed cell death associated with inflammation, neurodegeneration, and ischemia. Vitamin E (alpha-tocopherol) has been reported to prevent ferroptosis, but the mechanism by which this occurs is controversial. To elucidate the biochemical mechanism of vitamin E activity, we systematically investigated the effects of its major vitamers and metabolites on lipid oxidation and ferroptosis in a striatal cell model. We found that a specific endogenous metabolite of vitamin E, alpha-tocopherol hydroquinone, was a dramatically more potent inhibitor of ferroptosis than its parent compound, and inhibits 15-lipoxygenase via reduction of the enzyme’s non-heme iron from its active Fe3+ state to an inactive Fe2+ state. Furthermore, a non-metabolizable isosteric analog of vitamin E which retains antioxidant activity neither inhibited 15-lipoxygenase nor prevented ferroptosis. These results call into question the prevailing model that vitamin E acts predominantly as a non-specific lipophilic antioxidant. We propose that, similar to the other lipophilic vitamins A, D and K, vitamin E is instead a pro-vitamin, with its quinone/hydroquinone metabolites responsible for its anti-ferroptotic cytoprotective activity. [ABSTRACT FROM AUTHOR]