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GENE EXPRESSION PROFILING OF XENOBIOTIC METABOLIZING ENZYMES (XMES) IN THE AGING MALE FISHER RAT
Citation:
LEE, J. S., D. C. WOLF, J. W. ALLEN, W. O. WARD, AND C. CORTON. GENE EXPRESSION PROFILING OF XENOBIOTIC METABOLIZING ENZYMES (XMES) IN THE AGING MALE FISHER RAT. Presented at Society of Toxicology Annual Meeting 2007, Charlotte, NC, March 25 - 29, 2007.
Description:
Detoxification and elimination of xenobiotics is a major function of the liver and is important in maintaining the metabolic homeostasis of the organism. The degree to which aging affects hepatic metabolism is not known. The expression of XMEs, in part, determines the fate of the xenobiotic and whether exposure will result in toxicity. This project was designed to examine the changes in XMEs during the aging process in male Fisher rats. Gene expression profiles for XMEs in male Fisher rats (6, 11, 18, 24 months of age) were generated using Affymetrix Rat 230 2.0 arrays. Four animals per age group were profiled. Principal component analysis showed a clear age-dependent separation in expression profiles between 6 and 24 month hepatic transcripts. Differentially expressed genes (DEG) were identified using the following algorithm: background correction was performed using MAS5 followed by a quantile normalization, perfect match adjustment, median polish, Loess normalization and Cyber T statistics. 1135 genes were found to be significantly altered in a 24 versus 6 month comparison, and 155 genes were significantly altered in a 18 versus 6 month comparison. No significant gene changes were observed between 11 and 6 month old rats. In the 24 versus 6 month comparison, we found 23 phase I, 10 phase II, and 20 phase III metabolism genes significantly altered. In the 1 8 versus 6 month comparison, we found 3 phase I and 2 phase III metabolism genes significantly altered. qRT-PCR was performed to confirm altered expression. These data confirm an age-dependent change in XME gene expression in male Fisher rats. This information can be used to adapt pharmacokinetic models to reflect age-dependent differences in xenobiotic metabolism.