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GENE EXPRESSION PROFILING IN AGING RATS AND MICE REVEALS CHANGES IN XENOBIOTIC METABOLISM GENES
Citation:
LEE, J. S., D. C. WOLF, J. W. ALLEN, W. O. WARD, AND C. CORTON. GENE EXPRESSION PROFILING IN AGING RATS AND MICE REVEALS CHANGES IN XENOBIOTIC METABOLISM GENES. Presented at The 44th Congress of the European Societies of Toxicology, Amsterdam, NETHERLANDS, October 07 - 10, 2007.
Impact/Purpose:
This information will be used to adapt pharmacokinetic models to reflect age-dependent differences in xenobiotic metabolism.
Description:
Detoxification and elimination of xenobiotics are major functions 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 xenobiotic metabolizing enzymes (XMEs), in part, determines the fate of the xenobiotic and whether exposure will result in toxicity. We used Affymetrix chips to determine the changes in gene expression in aged (24 month old) male rats and mice compared to their young (4-6 months) counterparts focusing on XMEs and other categories of genes that can impact responses to chemicals. Rats and mice exhibit differences in the overall pattern of XMEs during aging with a greater impact in rats than mice. Aging had the greatest impact on Phase I and III genes in both species. As many of the altered genes are regulated by the growth hormone secretory pattern, the changes in expression indicate a general feminization of the male liver with age. In both mice and rats, aging altered the expression of genes involved in inflammation, proteome maintenance and lipid metabolism. Differences exist in the expression of the transcription factors that control many of these age-dependent genes including decreases in constitutive activated receptor (CAR) that controls many XMEs. This information will be used to adapt pharmacokinetic models to reflect age-dependent differences in xenobiotic metabolism.