Differential gene expression in mouse liver associated with the hepatoprotective effect of clofibrate

Journal Article · Sun Jul 15 04:00:00 EDT 2007 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2007.04.008· OSTI ID:20976984

Moffit, Jeffrey S ^[1]; Koza-Taylor, Petra H ^[2]; Holland, Ricky D ^[3]; Thibodeau, Michael S ^[1]; Beger, Richard D ^[3]; Lawton, Michael P ^[2]; Manautou, Jose E ^[1]

---

1. University of Connecticut, Department of Pharmaceutical Sciences, Storrs, CT (United States)
2. Pfizer, Inc., Groton Laboratories, Molecular and Investigative Toxicology, Groton, CT (United States)
3. National Center for Toxicological Research, Division of Systems Toxicology, Jefferson, AR (United States)

Pretreatment of mice with the peroxisome proliferator clofibrate (CFB) protects against acetaminophen (APAP)-induced hepatotoxicity. Previous studies have shown that activation of the nuclear peroxisome proliferator activated receptor-alpha (PPAR{alpha}) is required for this effect. The present study utilizes gene expression profile analysis to identify potential pathways contributing to PPAR{alpha}-mediated hepatoprotection. Gene expression profiles were compared between wild type and PPAR{alpha}-null mice pretreated with vehicle or CFB (500 mg/kg, i.p., daily for 10 days) and then challenged with APAP (400 mg/kg, p.o.). Total hepatic RNA was isolated 4 h after APAP treatment and hybridized to Affymetrix Mouse Genome MGU74 v2.0 GeneChips. Gene expression analysis was performed utilizing GeneSpring (registered) software. Our analysis identified 53 genes of interest including vanin-1, cell cycle regulators, lipid-metabolizing enzymes, and aldehyde dehydrogenase 2, an acetaminophen binding protein. Vanin-1 could be important for CFB-mediated hepatoprotection because this protein is involved in the synthesis of cysteamine and cystamine. These are potent antioxidants capable of ameliorating APAP toxicity in rodents and humans. HPLC-ESI/MS/MS analysis of liver extracts indicates that enhanced vanin-1 gene expression results in elevated cystamine levels, which could be mechanistically associated with CFB-mediated hepatoprotection.

• OSTI ID: 20976984
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 2 Vol. 222; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ALDEHYDES
ANTIOXIDANTS
CELL CYCLE
COMPUTER CODES
CYSTAMINE
CYSTEAMINE
ENZYMES
GENES
HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY
LIPIDS
LIVER
MICE
PANTOTHENIC ACID
RECEPTORS
RNA
TOXICITY