Chemical Activation of the Constitutive Androstane Receptor Leads to Activation of Oxidant-Induced Nrf2

Abstract

Exposure to environmentally-relevant chemicals that activate the xenobiotic receptors aryl hydrocarbon receptor (AhR), constitutive androstane receptor (CAR), and peroxisome proliferator-activated receptor alpha (PPARα) in rodent test systems often leads to increases in oxidative stress (OS) that contributes to liver cancer induction. We hypothesized that activation of the oxidant-induced transcription factor Nrf2 could be used as a surrogate endpoint for increases in OS. We examined the relationships between activation of xenobiotic receptors and Nrf2 using previously characterized gene expression biomarkers that accurately predict modulation. Using a correlation approach (Running Fisher Test), the biomarkers were compared to microarray profiles in a mouse liver gene expression compendium. Out of the 163 chemicals examined, 47% from 53 studies activated Nrf2. We found consistent coupling between CAR and Nrf2 activation. Out of the 41 chemicals from 32 studies that activated CAR, 90% also activated Nrf2. CAR was activated earlier and at lower doses than Nrf2, indicating CAR activation preceded Nrf2 activation. Nrf2 activation by two CAR activators was abolished in CAR-null mice. We hypothesized that Nrf2 is activated by ROS from the increased activity of enzymes encoded by Cyp2b family members. However, Nrf2 was similarly activated in the livers of both TCPOBOP-treated wild-type and Cyp2b9/10/13-null mice. This study provides evidence that Nrf2 activation 1) often occurs after exposure to xenobiotic chemicals, 2) is tightly linked to activation of CAR, and 3) does not require induction of three Cyp2b genes secondary to CAR activation.

Sex-, Age-, and Race/Ethnicity-Dependent Variations in Drug-Processing and NRF2-Regulated Genes in Human Livers

“…NAD(P)H:quinone oxidoreductase 1 (NQO1), peroxidase (PRDX1) (Kobayashi and Yamamoto, 2006), glutaredoxin (GLRX) (Holmgren et al, 2005), thioredoxin and thioredoxin reductase-1 (TXN, TXNRD1) (Lu and Holmgren, 2014), and epoxide hydrolase 1 (EH1) (Cornejo et al, 2013) play important roles in cellular detoxifying systems, and are also under NRF2 regulation. NRF2 activation induces a number of phase-II drug metabolizing enzymes directly and metabolic activities downstream of AhR (Yeager et al, 2009;Wu et al, 2012), or CAR activation (Rooney et al, 2019). The non-enzymatic thiol-rich protein metallothionein and its regulators (MTF-1, MT-1A, MT-2A) play important roles in heavy metal detoxification (Klaassen et al, 1999), and are also under influence of Nrf2 (Gu et al, 2017).…”

Mining a human transcriptome database for chemical modulators of NRF2

“…In summary, the present study is to our knowledge the first to utilize gene expression data to identify potential human NRF2 modulators in a large screening study. Using a similar approach, our group has recently identified chemicals that activate NRF2 in the mouse liver and compared the activation to conditions in which a number of xenobiotic-activated transcription factors are chemically activated [20,21,56].…”

“…One mechanism by which chemicals can exert toxic effects on a cell is by activating or repressing transcription factors, thus changing gene expression and altering normal cellular signaling events. We have previously developed gene expression biomarkers that can accurately identify chemicals that activate and/or suppress a number of transcription factors in the mouse or rat liver important in cancer and steatosis [11][12][13][14][15][16][17][18][19][20][21]. Our group has also characterized biomarkers that predict modulation of estrogen receptor (ERα) and androgen receptor or predict genotoxicity in human cells [22][23][24].…”

Constitutive Androstane Receptor and Hepatitis B Virus X Protein Cooperatively Induce β-catenin-Activated Liver Tumors

“…This raises the possibility that CAR may play an indirect role in β-catenin activation through the induction of FoxM1. FoxM1 and CAR are also each involved in promoting Nrf2 activation (29,31). Nrf2 mediates the antioxidant response and has been documented as an early driver of HCC (43).…”

“…Nrf2 promotes cell survival and proliferation in response to oxidative stress conditions, often an environment inherent in HCC development (23). Nrf2 activation is tightly linked to CAR activation, likely through CAR-mediated induction of oxidative stress (31). Additionally, Nrf2 activation can be stimulated by HBV infection, specifically by HBx activity.…”