1. Signaling by Keap1/Nrf2 mediates the electrophile response
Signaling by Keap1/Nrf2 mediates the electrophile response. Normally NF-E2-related factor 2 (Nrf2) is kept inactive and at a low intracellular level by interacting with Keap1, which promotes its proteosomal degradation by ubiquitination. Electrophiles covalently bind to, whereas oxidants oxidize, the reactive thiol groups of Keap1, causing Keap1 to release Nrf2. Alternatively, Nrf2 release may follow phosphorylation of Keap1 by protein kinases. After being released from Keap1, the active Nrf2 accumulates in the cell, translocates into the nucleus, and forms a heterodimer with small Maf proteins to activate genes that contain electrophile response element (EpRE) in their promoter region. These include enzymes, binding proteins, and transporters functioning in detoxication and elimination of xenobiotics, ROS, and endogenous reactive chemicals, as well as some proteins that can repair or eliminate oxidized proteins. Induction of such proteins represents an electrophile–stress response that provides protection against a wide range of toxicants. Abbreviations: AR = aldose reductase; G6PDH = glucose 6-phosphate dehydrogenase; GCL = glutamate-cysteine ligase; GGT = gamma-glutamyltranspeptidase; GPX2 = glutathione peroxidase 2; GR = glutathione reductase; GSTα = glutathione S-transferase α subunit; HO-1 = heme oxygenase 1; NQO1 = NAD(P)H:quinone oxidoreductase; NQO2 = NRH:quinone oxidoreductase; 2; Mrp2, Mrp3, and Mrp4 = multidrug-resistance protein 2, 3, and 4; SOD1 = superoxide dismutase 1; UGT = UDP-glucuronosyltransferase; Trx = thioredoxin; TrxR = thioredoxin reductase.
Source: Chapter 3. Mechanisms of Toxicity, Casarett & Doull's Essentials of Toxicology, 2e
Citation: Klaassen CD, Watkins JB, III. Casarett & Doull's Essentials of Toxicology, 2e; 2010 Available at: Accessed: October 30, 2017
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