Initial response and cellular protection through the Keap1/Nrf2 system during the exposure of primary mouse hepatocytes to 1,2-naphthoquinone

Takashi Miura, Yasuhiro Shinkai, Hai Yan Jiang, Noriko Iwamoto, Daigo Sumi, Keiko Taguchi, Masayuki Yamamoto, Hideto Jinno, Toshiko Tanaka-Kagawa, Arthur K. Cho, Yoshito Kumagai

研究成果: Article

45 引用 (Scopus)

抜粋

Quinones are reactive chemical species that cause cellular damage by modifying protein thiols and/or catalyzing the reduction of oxygen to reactive oxygen species, thereby promoting oxidative stress. Transcription factor Nrf2 plays a crucial role in cellular defense against electrophilic modification and oxidative stress. In studies using 1,2-naphthoquinone (1,2-NQ) as a model quinone, we found that Keap1, the negative regulator of Nrf2, was readily arylated at its reactive thiols by 1,2-NQ. Exposure of primary mouse hepatocytes to 1,2-NQ resulted in the activation of Nrf2 and the upregulation of some of Nrf2's downstream genes. This interaction was further investigated in hepatocytes from Nrf2 knockout mice in which the proteins responsible for the metabolism and excretion of 1,2-NQ are minimally expressed. The chemical modification of cellular proteins by 1,2-NQ was enhanced by Nrf2 deletion, resulting in increased toxicity. However, deletion of the negative regulatory protein, Keap1, drastically reduced the covalent binding by 1,2-NQ and its cellular toxicity. Experiments with chemicals that inhibit the biotransformation and extracellular excretion of 1,2-NQ suggest that 1,2-NQ undergoes detoxification and excretion into the extracellular space predominantly by two-electron reduction and subsequent glucuronidation by NAD(P)H:quinone oxidoreductase 1 and uridine 5′-diphosphate-glucuronosyltransferases, followed by multidrug resistance-associated protein-dependent excretion. These findings suggest that the Keap1/Nrf2 system is essential for the prevention of cell damage resulting from exposure to 1,2-NQ.

元の言語English
ページ(範囲)559-567
ページ数9
ジャーナルChemical Research in Toxicology
24
発行部数4
DOI
出版物ステータスPublished - 2011 4 18

ASJC Scopus subject areas

  • Toxicology

フィンガープリント Initial response and cellular protection through the Keap1/Nrf2 system during the exposure of primary mouse hepatocytes to 1,2-naphthoquinone' の研究トピックを掘り下げます。これらはともに一意のフィンガープリントを構成します。

  • これを引用