Interaction of Keap1 Modified by 2-tert-Butyl-1,4-benzoquinone with GSH: Evidence for S-Transarylation

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• 作者：Yumi Abiko ; Yoshito Kumagai
• 刊名：Chemical Research in Toxicology
• 出版年：2013
• 出版时间：July 15, 2013
• 年：2013
• 卷：26
• 期：7
• 页码：1080-1087
• 全文大小：450K
• 年卷期：v.26,no.7(July 15, 2013)
• ISSN：1520-5010

文摘

2-tert-Butyl-1,4-benzoquinone (TBQ), an electrophilic metabolite of butylated hydroxyanisole (BHA), causes activation of Nrf2 together with S-arylation of its negative regulator Keap1 in RAW264.7 cells. In a previous study, we found that glyceraldehyde-3-phosphate dehydrogenase (GAPDH) covalently modified with 1,2-naphthoquinone (1,2-NQ) undergoes S-transarylation by GSH, resulting in a decline of the GAPDH-1,2-NQ adduct and formation of a 1,2-NQ-SG adduct (Miura, T. et al. (2011) Chem. Res. Toxicol.24, 1836鈭?844). In the present study, we explored the possibility of GSH-dependent S-transarylation of the Keap1-TBQ adduct. Pretreatment with l-buthionine-(S,R)-sulfoximine and N-acetylcysteine prior to TBQ exposure of HepG2 cells suggested that the Keap1-TBQ adduct appears to undergo GSH-mediated S-transarylation because the resulting alterations in the intracellular GSH concentration affected Nrf2 activation caused by TBQ. In support of this hypothesis, a cell-free study demonstrated that incubation of the Keap1-TBQ adduct with GSH results in the removal of TBQ from Keap1 with the production of mono- and di-GSH adducts of TB(H)Q. These results suggest that GSH plays a role in reversible covalent modification of TBQ derived from BHA to Keap1 through the formation of a C鈥揝 bond.