Retinoid X Receptor α Regulates Glutathione Homeostasis and Xenobiotic Detoxification Processes in Mouse Liver

Yong Wu, Xiaoxue Zhang, Fawzia Bardag-Gorce, Rose C V Robel, Jonathan Aguilo, Lixin Chen, Ying Zeng, Kelly Hwang, Samuel W. French, Shelly C. Lu, Yu-Jui Yvonne Wan

Research output: Contribution to journalArticle

54 Citations (Scopus)

Abstract

Retinoid X receptor α (RXRα) plays a pivotal role in regulating liver metabolism. RXRα-mediated gene expression involved in amino acid metabolism was examined using the NIA Mouse 15K cDNA microarray containing 15,000 different expressed sequence tags. Seven amino acid metabolic genes, three of which encode enzymes involved in phase II detoxification process, were identified as RXRα target genes in mouse liver. Glutamate-cysteine ligase catalytic subunit (GCLC), glutathione S-transferaseμ, and glutathione peroxidase 1 were down-regulated in the liver of hepatocyte RXRα-deficient mice. The down-regulation of GCLC in RXRα-deficient mice led to 40% and 45% reductions in the rate of glutathione (GSH) synthesis and level of hepatic GSH, respectively. Primary hepatocytes from RXRα-deficient mice were more sensitive to t-butylhydroperoxide-induced oxidative stress. However, GSH diminished RXRα-deficient mice were resistant to acetaminophen (APAP)-induced hepatotoxicity. Analysis of phase I detoxification genes revealed that CYP1A2 and CYP3A11 were up-regulated in wild-type mice but down-regulated in RXRα-deficient mice after APAP administration. Taken together, the data indicate that RXRα centrally regulates both phase I and phase II drug metabolism and detoxification. Regulation of hepatic GSH levels by RXRα is essential to protect hepatocytes from oxidative stress, whereas up-regulation of phase I drug metabolism genes by RXRα may render the liver more sensitive to APAP-induced toxicity.

Original languageEnglish (US)
Pages (from-to)550-557
Number of pages8
JournalMolecular Pharmacology
Volume65
Issue number3
DOIs
StatePublished - Mar 2004
Externally publishedYes

Fingerprint

Retinoid X Receptors
Xenobiotics
Glutathione
Homeostasis
Liver
Acetaminophen
Phase II Metabolic Detoxication
Glutamate-Cysteine Ligase
Hepatocytes
Phase I Metabolic Detoxication
Genes
Catalytic Domain
Oxidative Stress
tert-Butylhydroperoxide
Amino Acids
Cytochrome P-450 CYP1A2
Expressed Sequence Tags
Oligonucleotide Array Sequence Analysis
Glutathione Transferase
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Pharmacology

Cite this

Retinoid X Receptor α Regulates Glutathione Homeostasis and Xenobiotic Detoxification Processes in Mouse Liver. / Wu, Yong; Zhang, Xiaoxue; Bardag-Gorce, Fawzia; Robel, Rose C V; Aguilo, Jonathan; Chen, Lixin; Zeng, Ying; Hwang, Kelly; French, Samuel W.; Lu, Shelly C.; Wan, Yu-Jui Yvonne.

In: Molecular Pharmacology, Vol. 65, No. 3, 03.2004, p. 550-557.

Research output: Contribution to journalArticle

Wu, Y, Zhang, X, Bardag-Gorce, F, Robel, RCV, Aguilo, J, Chen, L, Zeng, Y, Hwang, K, French, SW, Lu, SC & Wan, Y-JY 2004, 'Retinoid X Receptor α Regulates Glutathione Homeostasis and Xenobiotic Detoxification Processes in Mouse Liver', Molecular Pharmacology, vol. 65, no. 3, pp. 550-557. https://doi.org/10.1124/mol.65.3.550
Wu, Yong ; Zhang, Xiaoxue ; Bardag-Gorce, Fawzia ; Robel, Rose C V ; Aguilo, Jonathan ; Chen, Lixin ; Zeng, Ying ; Hwang, Kelly ; French, Samuel W. ; Lu, Shelly C. ; Wan, Yu-Jui Yvonne. / Retinoid X Receptor α Regulates Glutathione Homeostasis and Xenobiotic Detoxification Processes in Mouse Liver. In: Molecular Pharmacology. 2004 ; Vol. 65, No. 3. pp. 550-557.
@article{1f7b60fb2234428e9a776687f8c41892,
title = "Retinoid X Receptor α Regulates Glutathione Homeostasis and Xenobiotic Detoxification Processes in Mouse Liver",
abstract = "Retinoid X receptor α (RXRα) plays a pivotal role in regulating liver metabolism. RXRα-mediated gene expression involved in amino acid metabolism was examined using the NIA Mouse 15K cDNA microarray containing 15,000 different expressed sequence tags. Seven amino acid metabolic genes, three of which encode enzymes involved in phase II detoxification process, were identified as RXRα target genes in mouse liver. Glutamate-cysteine ligase catalytic subunit (GCLC), glutathione S-transferaseμ, and glutathione peroxidase 1 were down-regulated in the liver of hepatocyte RXRα-deficient mice. The down-regulation of GCLC in RXRα-deficient mice led to 40{\%} and 45{\%} reductions in the rate of glutathione (GSH) synthesis and level of hepatic GSH, respectively. Primary hepatocytes from RXRα-deficient mice were more sensitive to t-butylhydroperoxide-induced oxidative stress. However, GSH diminished RXRα-deficient mice were resistant to acetaminophen (APAP)-induced hepatotoxicity. Analysis of phase I detoxification genes revealed that CYP1A2 and CYP3A11 were up-regulated in wild-type mice but down-regulated in RXRα-deficient mice after APAP administration. Taken together, the data indicate that RXRα centrally regulates both phase I and phase II drug metabolism and detoxification. Regulation of hepatic GSH levels by RXRα is essential to protect hepatocytes from oxidative stress, whereas up-regulation of phase I drug metabolism genes by RXRα may render the liver more sensitive to APAP-induced toxicity.",
author = "Yong Wu and Xiaoxue Zhang and Fawzia Bardag-Gorce and Robel, {Rose C V} and Jonathan Aguilo and Lixin Chen and Ying Zeng and Kelly Hwang and French, {Samuel W.} and Lu, {Shelly C.} and Wan, {Yu-Jui Yvonne}",
year = "2004",
month = "3",
doi = "10.1124/mol.65.3.550",
language = "English (US)",
volume = "65",
pages = "550--557",
journal = "Molecular Pharmacology",
issn = "0026-895X",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "3",

}

TY - JOUR

T1 - Retinoid X Receptor α Regulates Glutathione Homeostasis and Xenobiotic Detoxification Processes in Mouse Liver

AU - Wu, Yong

AU - Zhang, Xiaoxue

AU - Bardag-Gorce, Fawzia

AU - Robel, Rose C V

AU - Aguilo, Jonathan

AU - Chen, Lixin

AU - Zeng, Ying

AU - Hwang, Kelly

AU - French, Samuel W.

AU - Lu, Shelly C.

AU - Wan, Yu-Jui Yvonne

PY - 2004/3

Y1 - 2004/3

N2 - Retinoid X receptor α (RXRα) plays a pivotal role in regulating liver metabolism. RXRα-mediated gene expression involved in amino acid metabolism was examined using the NIA Mouse 15K cDNA microarray containing 15,000 different expressed sequence tags. Seven amino acid metabolic genes, three of which encode enzymes involved in phase II detoxification process, were identified as RXRα target genes in mouse liver. Glutamate-cysteine ligase catalytic subunit (GCLC), glutathione S-transferaseμ, and glutathione peroxidase 1 were down-regulated in the liver of hepatocyte RXRα-deficient mice. The down-regulation of GCLC in RXRα-deficient mice led to 40% and 45% reductions in the rate of glutathione (GSH) synthesis and level of hepatic GSH, respectively. Primary hepatocytes from RXRα-deficient mice were more sensitive to t-butylhydroperoxide-induced oxidative stress. However, GSH diminished RXRα-deficient mice were resistant to acetaminophen (APAP)-induced hepatotoxicity. Analysis of phase I detoxification genes revealed that CYP1A2 and CYP3A11 were up-regulated in wild-type mice but down-regulated in RXRα-deficient mice after APAP administration. Taken together, the data indicate that RXRα centrally regulates both phase I and phase II drug metabolism and detoxification. Regulation of hepatic GSH levels by RXRα is essential to protect hepatocytes from oxidative stress, whereas up-regulation of phase I drug metabolism genes by RXRα may render the liver more sensitive to APAP-induced toxicity.

AB - Retinoid X receptor α (RXRα) plays a pivotal role in regulating liver metabolism. RXRα-mediated gene expression involved in amino acid metabolism was examined using the NIA Mouse 15K cDNA microarray containing 15,000 different expressed sequence tags. Seven amino acid metabolic genes, three of which encode enzymes involved in phase II detoxification process, were identified as RXRα target genes in mouse liver. Glutamate-cysteine ligase catalytic subunit (GCLC), glutathione S-transferaseμ, and glutathione peroxidase 1 were down-regulated in the liver of hepatocyte RXRα-deficient mice. The down-regulation of GCLC in RXRα-deficient mice led to 40% and 45% reductions in the rate of glutathione (GSH) synthesis and level of hepatic GSH, respectively. Primary hepatocytes from RXRα-deficient mice were more sensitive to t-butylhydroperoxide-induced oxidative stress. However, GSH diminished RXRα-deficient mice were resistant to acetaminophen (APAP)-induced hepatotoxicity. Analysis of phase I detoxification genes revealed that CYP1A2 and CYP3A11 were up-regulated in wild-type mice but down-regulated in RXRα-deficient mice after APAP administration. Taken together, the data indicate that RXRα centrally regulates both phase I and phase II drug metabolism and detoxification. Regulation of hepatic GSH levels by RXRα is essential to protect hepatocytes from oxidative stress, whereas up-regulation of phase I drug metabolism genes by RXRα may render the liver more sensitive to APAP-induced toxicity.

UR - http://www.scopus.com/inward/record.url?scp=10744223848&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=10744223848&partnerID=8YFLogxK

U2 - 10.1124/mol.65.3.550

DO - 10.1124/mol.65.3.550

M3 - Article

C2 - 14978233

AN - SCOPUS:10744223848

VL - 65

SP - 550

EP - 557

JO - Molecular Pharmacology

JF - Molecular Pharmacology

SN - 0026-895X

IS - 3

ER -