Abstract:
:Transcription factor NF-E2-related factor 2 (NRF2) plays a crucial role in the cellular defense against oxidative/electrophilic stress by up-regulating multiple antioxidant genes. Numerous studies with genetically modified animals have demonstrated that Nrf2 is a sensitivity determining factor upon the exposure to environmental chemicals including carcinogens. Moreover, recent studies have demonstrated that polymorphism in the human NRF2 promoter is associated with higher risks for developing acute lung injury, gastric mucosal inflammation, and nephritis. Therefore, the identification of reliable and effective human target genes of NRF2 may allow the monitoring of NRF2 activity and to predict individual sensitivity to environmental stress-induced damage. For this purpose, we investigated genes that are tightly controlled by NRF2 to establish markers for NRF2 activity in human cells. Firstly, in the normal human renal epithelial HK-2 cells, the measurement of the expression of 30 previously reported NRF2 target genes in response to NRF2 inducers (sulforaphane, tert-butylhydroquinone, cinnamic aldehyde, and hydrogen peroxide) showed that the aldo-keto reductase (AKR) 1C1 is highly inducible by all treatments. Accordantly, the basal and inducible expressions of AKRs were significantly attenuated in NRF2-silenced HK-2 cells. Whereas, cells with stable KEAP1 knockdown, which causes a modest NRF2 activation, demonstrated substantially increased levels of AKR1A1, 1B1, 1B10, 1C1, 1C2, and 1C3. Secondly, the linkage between NRF2 and the AKRs was confirmed in human monocytic leukemia cell line U937, which can be a model of peripherally available blood cells. The treatment of U937 cells with NRF2 inducers including sulforaphane effectively elevated the expression of AKR1B1, 1B10, 1C1, 1C2, and 1C3. Whereas, the levels of both the basal and sulforaphane-inducible expression of AKR1C1 were significantly reduced in NRF2-silenced stable U937 cells compared to the control cells. Similarly, the inducible expression of AKR1C1 was observed in another human monocytic leukemia cell line THP-1 as well as in human primary blood CD14(+) monocytes. In conclusion, together with the high inducibility and NRF2 dependency shown in renal epithelial cells as well as in peripherally available blood cells, current findings suggest that AKRs can be utilized as a marker of NRF2 activity in human cells.
journal_name
Toxicol Lettjournal_title
Toxicology lettersauthors
Jung KA,Choi BH,Nam CW,Song M,Kim ST,Lee JY,Kwak MKdoi
10.1016/j.toxlet.2012.12.026subject
Has Abstractpub_date
2013-03-27 00:00:00pages
39-49issue
1eissn
0378-4274issn
1879-3169pii
S0378-4274(13)00002-7journal_volume
218pub_type
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journal_title:Toxicology letters
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journal_title:Toxicology letters
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journal_title:Toxicology letters
pub_type: 杂志文章
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journal_title:Toxicology letters
pub_type: 杂志文章,评审
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journal_title:Toxicology letters
pub_type: 杂志文章
doi:10.1016/j.toxlet.2012.07.010
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journal_title:Toxicology letters
pub_type: 杂志文章
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journal_title:Toxicology letters
pub_type: 杂志文章
doi:10.1016/0378-4274(83)90137-6
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journal_title:Toxicology letters
pub_type: 杂志文章
doi:10.1016/j.toxlet.2018.03.015
更新日期:2018-06-01 00:00:00
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pub_type: 杂志文章
doi:10.1016/j.toxlet.2013.06.240
更新日期:2013-09-12 00:00:00
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pub_type: 杂志文章
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pub_type: 杂志文章
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journal_title:Toxicology letters
pub_type: 杂志文章
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journal_title:Toxicology letters
pub_type: 杂志文章
doi:10.1016/j.toxlet.2014.06.030
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journal_title:Toxicology letters
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journal_title:Toxicology letters
pub_type: 杂志文章
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journal_title:Toxicology letters
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journal_title:Toxicology letters
pub_type: 杂志文章
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更新日期:1998-12-28 00:00:00
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journal_title:Toxicology letters
pub_type: 杂志文章
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更新日期:2001-12-15 00:00:00
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journal_title:Toxicology letters
pub_type: 杂志文章,评审
doi:10.1016/0378-4274(95)03470-6
更新日期:1995-12-01 00:00:00
abstract::Intraperitoneal injection (50 mg/kg) of 2-nitropropane (2-NP) induced lipid accumulation, centrilobular necrosis, degranulation of rough endoplasmic reticulum, proliferation of smooth endoplasmic reticulum and mitochondrial abnormalities in rat liver 24 h after exposure. These pathological changes were accompanied by ...
journal_title:Toxicology letters
pub_type: 杂志文章
doi:10.1016/0378-4274(81)90156-9
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journal_title:Toxicology letters
pub_type: 杂志文章
doi:10.1016/0378-4274(85)90141-9
更新日期:1985-01-01 00:00:00
abstract::P-glycoprotein (Pgp) participates in the export of numerous toxins, drugs, and physiological compounds. To examine the involvement of Pgp in smoke-induced oral cell insult, the effects of extracts of the mainstream tobacco smoke (TS) on Pgp were studied in an oral epidermal carcinoma cell line, OECM-1. TS was first ex...
journal_title:Toxicology letters
pub_type: 杂志文章
doi:10.1016/j.toxlet.2008.12.007
更新日期:2009-03-10 00:00:00
abstract::The effect of dichlorophenoxyacetic acid on the transport of two non-metabolizable amino acids, 2-aminoisobutyric acid (AIB) and cycloleucine (CL) was studied in chinese hamster ovary (CHO) cells. The herbicide did not exert any direct effect on the AIB transport. However, when the pesticide was in contact with the ce...
journal_title:Toxicology letters
pub_type: 杂志文章
doi:10.1016/0378-4274(87)90184-6
更新日期:1987-04-01 00:00:00