Activation of the Nrf2 response by intrinsic hepatotoxic drugs correlates with suppression of NF-kappa B activation and sensitizes toward TNF alpha-induced cytotoxicity

作者：Herpers Bram; Wink Steven; Fredriksson Lisa; Di Zi; Hendriks Giel; Vrieling Harry; de Bont Hans; van de Water Bob^*

来源：Archives of Toxicology, 2016, 90(5): 1163-1179.

DOI：10.1007/s00204-015-1536-3

• Drug-induced liver injury
• Live-cell imaging
• Nrf2 activation
• Oxidative stress
• NF-kappa B signaling

Drug-induced liver injury (DILI) is an important problem both in the clinic and in the development of new safer medicines. Two pivotal adaptation and survival responses to adverse drug reactions are oxidative stress and cytokine signaling based on the activation of the transcription factors Nrf2 and NF-kappa B, respectively. Here, we systematically investigated Nrf2 and NF-kappa B signaling upon DILI-related drug exposure. Transcriptomics analyses of 90 DILI compounds in primary human hepatocytes revealed that a strong Nrf2 activation is associated with a suppression of endogenous NF-kappa B activity. These responses were translated into quantitative high-content live-cell imaging of induction of a selective Nrf2 target, GFP-tagged Srxn1, and the altered nuclear translocation dynamics of a subunit of NF-kappa B, GFP-tagged p65, upon TNFR signaling induced by TNF alpha using HepG2 cells. Strong activation of GFP-Srxn1 expression by DILI compounds typically correlated with suppression of NF-kappa B nuclear translocation, yet reversely, activation of NF-kappa B by TNF alpha did not affect the Nrf2 response. DILI compounds that provided strong Nrf2 activation, including diclofenac, carbamazepine and ketoconazole, sensitized toward TNF alpha-mediated cytotoxicity. This was related to an adaptive primary protective response of Nrf2, since loss of Nrf2 enhanced this cytotoxic synergy with TNF alpha, while KEAP1 downregulation was cytoprotective. These data indicate that both Nrf2 and NF-kappa B signaling may be pivotal in the regulation of DILI. We propose that the NF-kappa B-inhibiting effects that coincide with a strong Nrf2 stress response likely sensitize liver cells to pro-apoptotic signaling cascades induced by intrinsic cytotoxic pro-inflammatory cytokines.

• 出版日期2016-5