Retinoid X Receptor α Regulates the Expression of Glutathione S-transferase Genes and Modulates Acetaminophen-Glutathione Conjugation in Mouse Liver

Abstract

Nuclear receptors, including constitutive androstane receptor, pregnane X receptor, and retinoid X receptor (RXR), modulate acetaminophen (APAP)-induced hepatotoxicity by regulating the expression of phase I cytochrome P450 (P450) genes. It has not been fully resolved, however, whether they regulate APAP detoxification at the phase II level. The aim of the current study was to evaluate the role of RXR␣ in phase II enzyme-mediated detoxification of APAP. Wild-type and hepatocyte-specific RXR␣ knockout mice were treated with a toxic dose of APAP (500 mg/kg i.p.). Mutant mice were protected from APAPinduced hepatotoxicity, even though basal liver glutathione (GSH) levels were significantly lower in mutant mice compared with those of wild-type mice. High-performance liquid chromatography analysis of APAP metabolites revealed significantly greater levels of APAP-GSH conjugates in livers and bile of mutant mice compared with those of wild-type mice. Furthermore, hepatocyte RXR␣ deficiency altered the gene expression profile of the glutathione S-transferase (Gst) family. Basal expression of 13 of 15 Gst genes studied was altered in hepatocyte-specific RXR␣-deficient mice. This probably led to enhanced APAP-GSH conjugation and reduced accumulation of N-acetyl-p-benzoquinone imine, a toxic electrophile that is produced by biotransformation of APAP by phase I P450 enzymes. In conclusion, the data presented in this study define an RXR␣-Gst regulatory network that controls APAP-GSH conjugation. This report reveals a potential novel strategy to enhance the detoxification of APAP or other xenobiotics by manipulating Gst activity through RXR␣-mediated pathways.

RXRα Inhibits the NRF2-ARE Signaling Pathway through a Direct Interaction with the Neh7 Domain of NRF2

“…In the present study, we showed that Nrf2 and RXRa interact in vivo. In agreement with our observation, Dai and colleagues (44) reported that in hepatocyte-specific RXRa knockout mice, the expression of Gsta1 and/or Gsta2, Gstm1 and/or Gstm3, Gstm2 and Gstm4, all of which are regulated by NRF2 (29,30,44), were increased compared with their levels in the liver of wild-type mice, presumably due to loss of NRF2 suppression. Moreover, the expression of these Gst subunits from hepatocyte-specific RXRa knockout mice was further enhanced by acetaminophen, whose hepatotoxic metabolite was able to directly activate the KEAP1-NRF2 pathway (45), showing RXRa represses NRF2/ARE signalling pathway in vivo.…”

Interplay of β-Catenin with Xenobiotic-Sensing Receptors and its Role in Glutathione S-Transferase Expression

“…In the latter publication, we were able to demonstrate that a RXR/VDR heterodimer binding site in the 5'-regulatory region of the murine Gstm3 gene, which had been identified by in silico analysis, is crucial for the transcriptional induction of mGstm3 promoter-driven reporter gene activity by -catenin [36]. This is in line with the abovementioned results by [99] demonstrating a loss of Gstm3 expression in RXR knockout mice.…”

“…Micromolar concentrations, however, of retinoids directly inhibit GST enzyme activity independent of retinoid receptors in vitro [98]. Hepatocytespecific knockout of the RXR gene alters the expression of a large panel of GSTs, with some isoforms being down-and others being up-regulated in the transgenic mice [99]. Notably, expression of GSTm protein and mRNA is down-regulated in that mouse model [100].…”

Empirical Data Confirm Autism Symptoms Related to Aluminum and Acetaminophen Exposure

“…Glutathione [23] and sulfate [24] are also essential for the detoxification of xenobiotics and commonly administered drugs like acetaminophen in the liver. Selenium, a trace metal in the same column of the periodic table as oxygen and sulfur, has been shown to protect against acetaminophen toxicity [25], and it has also been shown to be severely depleted in hair and nail samples from individuals on the autism spectrum [26].…”