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GENE EXPRESSION PROFILING OF XENOBIOTIC METABOLIZING ENZYMES (XMES) THROUGH THE LIFE STAGES OF THE MALE C57BL/6 MOUSE
Citation:
LEE, J. S., W. O. WARD, H. REN, R. GRINDSTAFF, M. H. GEORGE, D. A. DELKER, AND C. CORTON. GENE EXPRESSION PROFILING OF XENOBIOTIC METABOLIZING ENZYMES (XMES) THROUGH THE LIFE STAGES OF THE MALE C57BL/6 MOUSE. Presented at Society of Toxicology Annual Meeting, Seattle, WA, March 16 - 20, 2008.
Impact/Purpose:
This project was designed to examine the changes in XMEs from early to late life stages in male C57BL/6 mice.
Description:
In the presence of foreign compounds, metabolic homeostasis of the organism is maintained by the liver's ability to detoxify and eliminate these xenobiotics. This is accomplished, in part, by the expression of XMEs, which metabolize xenobiotics and determine whether exposure will result in toxicity. Some evidence indicates aging may alter the ability of organisms to process xenobiotics, but the degree to which aging affects hepatic metabolism is not known. This project was designed to examine the changes in XMEs from early to late life stages in male C57BL/6 mice. Gene expression profiles for XMEs were generated using Affymetrix Mouse 430 2.0 arrays for early (GD19, PD7, PD32, PD67) and older (2, 6, 12, 18, 24 months) life stages. Four animals per age group were profiled. Principal component analysis showed a clear age-dependent separation in expression profiles between GD19 and PD7 hepatic transcripts. Differentially expressed genes were identified using the following algorithm: background correction was performed using MAS5.0 followed by a quantile normalization, perfect match adjustment, median polish, LOESS normalization and Bayesian regression. An FDR of 0.05 was applied. Gene expression changes are the most abundant at the early time points (GD19 and PD7) and 24 months. No significant gene changes were observed between 6 and 2 month old mice. We found 365, 286, and 96 XMEs significantly altered in the GD19, PD7, and PD32 when compared to PD67 respectively. We found 69, 94, and 130 XMEs significantly altered in the 12, 18, and 24 months versus 2 months comparison respectively. qRT-PCR was performed to confirm altered expression. These data confirm age-dependent changes in XME gene expression in male C57BL/6 mice. This information can be used to adapt pharmacokinetic models to reflect age-dependent differences in xenobiotic metabolism.