Retinoid X receptor α regulates the expression of glutathione S-transferase genes and modulates acetaminophen-glutathione conjugation in mouse liver

Guoli Dai, Nathan Chou, Lin He, Maxwell A. Gyamfi, Alphonse J. Mendy, Angela L. Slitt, Curtis D. Klaassen, Yu-Jui Yvonne Wan

Research output: Contribution to journalArticle

26 Citations (Scopus)

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 RXRα in phase II enzyme-mediated detoxification of APAP. Wild-type and hepatocyte-specific RXRα knockout mice were treated with a toxic dose of APAP (500 mg/kg i.p.). Mutant mice were protected from APAP-induced 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 RXRα 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 RXRα-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 RXRα-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 RXRα-mediated pathways.

Original languageEnglish (US)
Pages (from-to)1590-1596
Number of pages7
JournalMolecular Pharmacology
Volume68
Issue number6
DOIs
StatePublished - Dec 2005
Externally publishedYes

Fingerprint

Retinoid X Receptors
Acetaminophen
Glutathione Transferase
Liver
Genes
Hepatocytes
Poisons
Cytochrome P-450 Enzyme System
3-(glutathion-S-yl)acetaminophen
Phase II Metabolic Detoxication
Imines
Xenobiotics
Cytoplasmic and Nuclear Receptors
Biotransformation
Transcriptome
Knockout Mice
Bile
Glutathione

ASJC Scopus subject areas

  • Pharmacology

Cite this

Retinoid X receptor α regulates the expression of glutathione S-transferase genes and modulates acetaminophen-glutathione conjugation in mouse liver. / Dai, Guoli; Chou, Nathan; He, Lin; Gyamfi, Maxwell A.; Mendy, Alphonse J.; Slitt, Angela L.; Klaassen, Curtis D.; Wan, Yu-Jui Yvonne.

In: Molecular Pharmacology, Vol. 68, No. 6, 12.2005, p. 1590-1596.

Research output: Contribution to journalArticle

Dai, Guoli ; Chou, Nathan ; He, Lin ; Gyamfi, Maxwell A. ; Mendy, Alphonse J. ; Slitt, Angela L. ; Klaassen, Curtis D. ; Wan, Yu-Jui Yvonne. / Retinoid X receptor α regulates the expression of glutathione S-transferase genes and modulates acetaminophen-glutathione conjugation in mouse liver. In: Molecular Pharmacology. 2005 ; Vol. 68, No. 6. pp. 1590-1596.
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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 RXRα in phase II enzyme-mediated detoxification of APAP. Wild-type and hepatocyte-specific RXRα knockout mice were treated with a toxic dose of APAP (500 mg/kg i.p.). Mutant mice were protected from APAP-induced 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 RXRα 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 RXRα-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 RXRα-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 RXRα-mediated pathways.",
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AU - He, Lin

AU - Gyamfi, Maxwell A.

AU - Mendy, Alphonse J.

AU - Slitt, Angela L.

AU - Klaassen, Curtis D.

AU - Wan, Yu-Jui Yvonne

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AB - 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 RXRα in phase II enzyme-mediated detoxification of APAP. Wild-type and hepatocyte-specific RXRα knockout mice were treated with a toxic dose of APAP (500 mg/kg i.p.). Mutant mice were protected from APAP-induced 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 RXRα 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 RXRα-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 RXRα-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 RXRα-mediated pathways.

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