Essential role of Nrf2 in protection against hydroquinone- and benzoquinone-induced cytotoxicity.
Benzene is a well-established human carcinogen. Benzene metabolites hydroquinone (HQ) and benzoquinone (BQ) are highly reactive molecules capable of producing reactive oxygen species and causing oxidative stress. In this study, we investigated the role of the Nrf2, a key nuclear transcription factor that regulates antioxidant response element (ARE)-containing genes, in defense against HQ- and BQ-induced cytotoxicity in cultured human lung epithelial cells (Beas-2B). When the cells were exposed to HQ or BQ the activity of an ARE reporter was induced in a dose-dependent manner, meanwhile Nrf2 protein levels were elevated and accumulated in the nucleus. Increased expression of well-known Nrf2-dependent proteins including NQO1, GCLM, GSS and HMOX was also observed in the HQ/BQ-treated cells. Moreover, transient overexpression of Nrf2 conferred protection against HQ- and BQ-induced cell death, whereas knockdown of Nrf2 by small interfering RNA resulted in increased apoptosis. We also found that the increased susceptibility of Nrf2-knockdown cells to HQ and BQ was associated with reduced glutathione levels and loss of inducibility of ARE-driven genes, suggesting that deficiency of Nrf2 impairs cellular redox capacity to counteract oxidative damage. Altogether, these results suggest that Nrf2-ARE pathway is essential for protection against HQ- and BQ-induced toxicity.
Departamento de Medicina Genómica y Toxicología Ambiental, Universidad Nacional Autónoma de México, México DF, Mexico.
Valentina
V
Rubio
Jiawei
J
Zhang
Mahara
M
Valverde
Emilio
E
Rojas
Zheng-Zheng
ZZ
Shi
D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D016227:Benzoquinones / Q000633:toxicity*; D002478:Cells, Cultured; D019610:Cytoprotection; D005978:Glutathione / Q000032:analysis; D006801:Humans; D006873:Hydroquinones / Q000633:toxicity*; D051267:NF-E2-Related Factor 2 / Q000502:physiology*; D020218:Response Elements / Q000502:physiology
D000975:Antioxidants; D016227:Benzoquinones; D006873:Hydroquinones; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C004532:quinone; D005978:Glutathione; C031927:hydroquinone