Cytoprotective role of Nrf2/Keap1 system in methylmercury toxicity.
Human exposure to methylmercury (MeHg) from contaminated fish is a potential health risk. Because of its chemical properties as a soft electrophile, we investigated the participation of Nrf2 in the cellular response to and protection against MeHg with SH-SY5Y cells and with primary mouse hepatocytes from Nrf2- and Keap1-deficient mice. Exposure of SH-SY5Y cells to MeHg activated Nrf2 through the binding of MeHg and Keap1. Nrf2 overexpression attenuated MeHg-induced cytotoxicity in SH-SY5Y cells. In addition, primary mouse hepatocytes extracted from Nrf2-deficient mouse was susceptible, and hepatocyte-specific conditional Keap1-deficient mouse was resistant to MeHg-induced cytotoxicity. Consistent with this data, MeHg was accumulated by Nrf2 deficiency and reduced by Keap1 deficiency. Our findings indicate that MeHg activates Nrf2 and the activation of Nrf2 is essential for reduction of MeHg toxicity by facilitating its excretion into extracellular space.
Toyama
Takashi
T
Master's Program in Environmental Sciences, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki 305-8572, Japan.
Sumi
Daigo
D
Shinkai
Yasuhiro
Y
Yasutake
Akira
A
Taguchi
Keiko
K
Tong
Kit I
KI
Yamamoto
Masayuki
M
Kumagai
Yoshito
Y
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D000072019:Kelch-Like ECH-Associated Protein 1; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008767:Methylmercury Compounds / Q000378:metabolism / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D008767:Methylmercury Compounds; D051267:NF-E2-Related Factor 2; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D008156:Luciferases