Low-Dose Dose-Response for In Vitro Nrf2-ARE Activation in Human HepG2 Cells
Kelch-like ECH-associated protein 1 (Keap1), nuclear factor erythroid 2-like factor 2-related factor 2 (Nrf2), and the antioxidant response element (ARE) are interacting components of a master regulatory signaling pathway that coordinates redox homeostasis, cytoprotective responses, and shifts in st...
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| Format: | Book |
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SAGE Publishing,
2017-04-01T00:00:00Z.
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| Summary: | Kelch-like ECH-associated protein 1 (Keap1), nuclear factor erythroid 2-like factor 2-related factor 2 (Nrf2), and the antioxidant response element (ARE) are interacting components of a master regulatory signaling pathway that coordinates redox homeostasis, cytoprotective responses, and shifts in stem cell state. This study reexamined detailed dose-response (DR) data reported for in vitro Nrf2-ARE activation in human hepatoblastoma HepG2 cell lines containing either a ARE- bla or ARE- luc reporter at 12 different concentrations of each of 15 chemicals. The normalized study data were combined among chemicals exhibiting a positive response, yielding n = 531 (179) DR data for 9 (7) chemicals using the ARE- bla (ARE- luc ) assay. Three-parameter linear/ k th-power regression fits obtained to each combined set of ARE- bla - or ARE- luc -assay response data provided good fits ( R 2 = .99 or .91, respectively, P fit > .99) that each incorporate a highly significant negative initial linear slope ( P = 4 × 10 −5 or .00025) and an overall J-shaped DR pattern. Results from this reanalysis of high-resolution ARE response data support the hypothesis that nonlinear ARE-mediated adaptive cellular responses to oxidative stress are governed by an ultrasensitive molecular switch. |
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| Item Description: | 1559-3258 10.1177/1559325817699696 |