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 language | English (US) |
|---|---|
| Pages (from-to) | 550-557 |
| Number of pages | 8 |
| Journal | Molecular Pharmacology |
| Volume | 65 |
| Issue number | 3 |
| DOIs | |
| State | Published - Mar 2004 |
| Externally published | Yes |
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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 journal › Article
}
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 -