Role of nuclear factor-erythroid 2-related factor 2 (Nrf2) in the transcriptional regulation of brain ABC transporters during acute acetaminophen (APAP) intoxication in mice

Ghanem, Carolina Inés; Rudraiah, Swetha; Bataille, Amy M.; Vigo, María Belén; Goedken, Michael; Manautou, José E.

doi:10.1016/j.bcp.2015.01.013

Cited by 29 publications

(22 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Upon activation by enhanced ROS production or electrophilic conditions, Nrf2 dissociates from Keap1, migrates into the nucleus and activates the expression of target genes by binding to ARE elements in the promoter of target genes (Bataille and Manautou 2012). Nrf2 has been shown to modulate the expression of antioxidant enzymes (Noh et al 2015) and Mrp2 (Ghanem et al 2015) after treatment with toxic acetaminophen doses in animal models. We report here for the first time a time-dependent stimulation of nuclear Nrf2 translocation by BZL that represents a clear evidence of Nrf2 activation and strongly suggests a role of Nrf2 in the regulation of antioxidant systems and MRP2 by BZL.…”

Section: Discussionmentioning

confidence: 99%

“…A colony of these Nrf2 −/− mice is maintained at The University of Connecticut. All mice were housed in a 12 h dark/light cycle in a temperature and humidity controlled environment and fed normal chow and water ad libitum throughout the study (Ghanem et al 2015). This work was conducted under the University of Connecticut’s Institutional Animal Care and Use Committee approved protocol number A12-050.…”

Section: Methodsmentioning

confidence: 99%

“…cDNA was synthesized using a M-MLV RT Kit (Life Technologies). The expression of Abcc2 was quantified with SYBR green using specific primers by the ΔΔCt method and normalized to the expression of β-actin as housekeeping gene using an Applied Biosystems 7500 Fast Real-Time PCR system as described (Ghanem et al 2015). Results were expressed as percentage of the control within each group.…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

The trypanocidal benznidazole promotes adaptive response to oxidative injury: Involvement of the nuclear factor-erythroid 2-related factor-2 (Nrf2) and multidrug resistance associated protein 2 (MRP2)

Rigalli

Perdomo

Ciriaci

et al. 2016

Toxicology and Applied Pharmacology

View full text Add to dashboard Cite

Oxidative stress is a frequent cause underlying drug-induced hepatotoxicity. Benznidazole (BZL) is the only antitripanocide agent available for treatment of Chagas disease in endemic areas. Its use is associated with side effects, including increases in biomarkers of hepatotoxicity. However, BZL potential to cause oxidative stress has been poorly investigated. Here, we evaluated the effect of a pharmacologically relevant BZL concentration (200 μM) at different time points on redox status and the counteracting mechanisms in the human hepatic cell line HepG2. BZL increased reactive oxygen species (ROS) after 1 and 3 h of exposure, returning to normality at 24 h. Additionally, BZL increased glutathione peroxidase activity at 12 h and the oxidized glutathione/total glutathione (GSSG/GSSG+GSH) ratio that reached a peak at 24 h. Thus, an enhanced detoxification of peroxide and GSSG formation could account for ROS normalization. GSSG/GSSG+GSH returned to control values at 48 h. Expression of the multidrug resistance-associated protein 2 (MRP2) and GSSG efflux via MRP2 were induced by BZL at 24 and 48 h, explaining normalization of GSSG/GSSG+GSH. BZL activated the nuclear erythroid 2-related factor 2 (Nrf2), already shown to modulate MRP2 expression in response to oxidative stress. Nrf2 participation was confirmed using Nrf2-knockout mice in which MRP2 mRNA expression was not affected by BZL. In summary, we demonstrated a ROS increase by BZL in HepG2 cells and a glutathione peroxidase- and MRP2 driven counteracting mechanism, being Nrf2 a key modulator of this response. Our results could explain hepatic alterations associated with BZL therapy.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

The trypanocidal benznidazole promotes adaptive response to oxidative injury: Involvement of the nuclear factor-erythroid 2-related factor-2 (Nrf2) and multidrug resistance associated protein 2 (MRP2)

Rigalli

Perdomo

Ciriaci

et al. 2016

Toxicology and Applied Pharmacology

View full text Add to dashboard Cite

show abstract

“…Brain mRNA and protein expression of Nqo1 increased at 24 h after APAP administration, while Ho-1 mRNA levels increased as early as 6h (Figure 5) (127). The different temporal induction profiles of these two genes is likely due to differences in regulatory events.…”

Section: Paradoxical Effects On the Brain: Protective Vs Toxic Actmentioning

confidence: 99%

“…Recently, our laboratories have demonstrated increased accumulation of Nrf2 in brain nuclei during APAP intoxication in mice. This is indicative of in situ oxidative stress and/or generation of APAP’s reactive intermediate and a disruption in brain redox balance sufficient enough to be detected by this oxidative stress sensor (Figure 4)(127). …”

Section: Paradoxical Effects On the Brain: Protective Vs Toxic Actmentioning

confidence: 99%

Acetaminophen from liver to brain: New insights into drug pharmacological action and toxicity

Ghanem

Pérez

Manautou

et al. 2016

Pharmacological Research

Self Cite

287

232

View full text Add to dashboard Cite

Acetaminophen (APAP) is a well-known analgesic and antipyretic drug. It is considered to be safe when administered within its therapeutic range, but in cases of acute intoxication, hepatotoxicity can occur. APAP overdose is the leading cause of acute liver failure in the northern hemisphere. Historically, studies on APAP toxicity have been focused on liver, with alterations in brain function attributed to secondary effects of acute liver failure. However, in the last decade the pharmacological mechanism of APAP as a cannabinoid system modulator has been documented and some articles have reported “in situ” toxicity by APAP in brain tissue at high doses. Paradoxically, low doses of APAP have been reported to produce the opposite, neuroprotective effects. In this paper we present a comprehensive, up-to-date overview of hepatic toxicity as well as a thorough review of both toxic and beneficial effects of APAP in brain.

show abstract

Low oxygen tension differentially regulates the expression of placental solute carriers and ABC transporters

Gorczyca

Bircsak

et al. 2020

FEBS Letters

View full text Add to dashboard Cite

Low oxygen concentration, or hypoxia, is an important physiological regulator of placental function including chemical disposition. Here, we compared the ability of low oxygen tension to alter the expression of solute carriers (SLC) and ABC transporters in two human placental models, namely BeWo cells and term placental explants. We found that exposure to low oxygen concentration differentially regulates transporter expression in BeWo cells, including downregulation of ENT1, OATP4A1, OCTN2, BCRP, and MRP2/3/5, and upregulation of CNT1, OAT4, OATP2B1, SERT, SOAT, and MRP1. Similar upregulation of MRP1 and downregulation of MRP5 and BCRP were observed in explants, whereas uptake transporters were decreased or unchanged. Furthermore, a screening of transcriptional regulators of transporters revealed that hypoxia leads to a decrease in the mRNA levels of aryl hydrocarbon receptor, nuclear factor erythroid 2‐related factor 2, and retinoid x receptor alpha in both human placental models. These data suggest that transporter expression is differentially regulated by oxygen concentration across experimental human placental models.

show abstract

Role of nuclear factor-erythroid 2-related factor 2 (Nrf2) in the transcriptional regulation of brain ABC transporters during acute acetaminophen (APAP) intoxication in mice

Cited by 29 publications

References 53 publications

The trypanocidal benznidazole promotes adaptive response to oxidative injury: Involvement of the nuclear factor-erythroid 2-related factor-2 (Nrf2) and multidrug resistance associated protein 2 (MRP2)

The trypanocidal benznidazole promotes adaptive response to oxidative injury: Involvement of the nuclear factor-erythroid 2-related factor-2 (Nrf2) and multidrug resistance associated protein 2 (MRP2)

Acetaminophen from liver to brain: New insights into drug pharmacological action and toxicity

Low oxygen tension differentially regulates the expression of placental solute carriers and ABC transporters

Contact Info

Product

Resources

About