Gene expression profiles of murine fatty liver induced by the administration of methotrexate.
Methotrexate (MTX) is used to treat a variety of chronic inflammatory and neoplastic diseases. However, it can induce hepatotoxicity such as microvesicular steatosis and necrosis. To explore the mechanisms of MTX-induced hepatic steatosis, we used microarray analysis to profile the gene expression patterns of mouse liver after MTX treatment. MTX was administered orally as a single dose of 10mg/kg (low dose) or 100 mg/kg (high dose) to ICR mice, and the livers were obtained 6 h, 24 h, and 72 h after treatment. Serum alanine aminotransferase, aspartate aminotransferase and triacylglycerol levels were not significantly altered in the experimental animals. Signs of steatosis were observed at 24 h after administration of high dose of MTX. From microarray data analysis, 908 genes were selected as MTX-responsive genes (P<0.05, two-way ANOVA; cutoff > or =1.5-fold). Database for Annotation, Visualization and Integrated Discovery (DAVID) analysis revealed that the predominant biological processes associated with these genes are response to unfolded proteins, phosphate metabolism, and cellular lipid metabolism. Functional categorization of these genes identified 28 genes involved in lipid metabolism that was interconnected with the biological pathways of biosynthesis, catabolism, and transport of lipids and fatty acids. Taken together, these data provide a better understanding of the molecular mechanisms of MTX-induced steatogenic hepatotoxicity, and useful information for predicting hepatotoxicity through pattern recognition.
Lee
Min-Ho
MH
College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
Hong
Il
I
Kim
Mingoo
M
Lee
Byung-Hoon
BH
Kim
Ju-Han
JH
Kang
Kyung-Sun
KS
Kim
Hyung-Lae
HL
Yoon
Byung-Il
BI
Chung
Heekyoung
H
Kong
Gu
G
Lee
Mi-Ock
MO
D000284:Administration, Oral; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000633:toxicity*; D005234:Fatty Liver / Q000139:chemically induced* / Q000235:genetics* / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D050356:Lipid Metabolism / Q000235:genetics*; D008297:Male; D008727:Methotrexate / Q000633:toxicity*; D051379:Mice; D008813:Mice, Inbred ICR; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000378:metabolism; D043922:Toxicogenetics
D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D008727:Methotrexate