Hepatic gene expression profiling and lipid homeostasis in mice exposed to steatogenic drug, tetracycline.
Tetracycline is one of a group of drugs known to induce microvesicular steatosis. In the present study, we investigated the effects of tetracycline on gene expression in mouse liver, using Applied Biosystems Mouse Genome Survey Microarrays. A single oral dose of 0.1 or 1 g/kg tetracycline was administered to male ICR mice, and liver samples were obtained after 6, 24, or 72 h. Histopathological evaluation showed microvesicular steatosis in the high-dose group at 24 h. In total, 96 genes were identified as tetracycline responsive. Their level of expression differed significantly from controls (two-way analysis of variance; p < 0.05), after adjustment by the Benjamini-Hochberg multiple testing correction, and displayed a twofold or greater induction or repression. The largest groups of gene products affected by tetracycline exposure were those involved in signal transduction, nucleic acid metabolism, developmental processes, and protein metabolism. The expression of genes known to be involved in lipid metabolism was examined, using two-sample Student's t-test for each treatment group versus a corresponding control group. The overall net effects on expression of lipid metabolism genes indicated an increase in cholesterol and triglyceride biosynthesis and a decrease in beta-oxidation of fatty acids. Our data support a proposed mechanism for tetracycline-induced steatogenic hepatotoxicity that involves these processes. Moreover, we demonstrated global changes in hepatic gene expression following tetracycline exposure; many of these genes have the potential to be used as biomarkers of exposure to steatogenic hepatotoxic agents.
Yin
Hu-Quan
HQ
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Republic of Korea.
Kim
Mingoo
M
Kim
Ju-Han
JH
Kong
Gu
G
Lee
Mi-Ock
MO
Kang
Kyung-Sun
KS
Yoon
Byung-Il
BI
Kim
Hyung-Lae
HL
Lee
Byung-Hoon
BH
D000284:Administration, Oral; D000704:Analysis of Variance; D000818:Animals; D016000:Cluster Analysis; D004305:Dose-Response Relationship, Drug; D005234:Fatty Liver / Q000139:chemically induced / Q000235:genetics*; D020869:Gene Expression Profiling; D006706:Homeostasis / Q000187:drug effects / Q000235:genetics; D050356:Lipid Metabolism / Q000187:drug effects* / Q000235:genetics; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D011500:Protein Synthesis Inhibitors / Q000008:administration & dosage / Q000633:toxicity; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D015398:Signal Transduction / Q000235:genetics; D013752:Tetracycline / Q000008:administration & dosage / Q000633:toxicity*; D013997:Time Factors
D011500:Protein Synthesis Inhibitors; D013752:Tetracycline