ToxSci Advance Access originally published online on August 17, 2006
Toxicological Sciences 2006 94(1):206-216; doi:10.1093/toxsci/kfl078
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Hepatic Gene Expression Profiling and Lipid Homeostasis in Mice Exposed to Steatogenic Drug, Tetracycline
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* College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Republic of Korea
Seoul National University Biomedical Informatics, College of Medicine, Seoul National University, Seoul 110-799, Republic of Korea
Human Genome Research Institute, College of Medicine, Seoul National University, Seoul 110-799, Republic of Korea
College of Medicine, Hanyang University, Seoul133-791, Republic of Korea
¶ College of Veterinary Medicine, Seoul National University, Seoul 151-742, Republic of Korea
|| College of Veterinary Medicine, Kangwon National University, Chuncheon 200-791, Republic of Korea
||| College of Medicine, Ewha Womans University, Seoul 158-710, Republic of Korea
Received May 30, 2006; accepted August 3, 2006
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 ß-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.
Key Words: tetracycline; microvesicular steatosis; toxicogenomics; lipid metabolism; microarray.