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Xenobiotic metabolizing enzyme (XME) expression in aging humans.
Citation:
Lee, J. S., W. O. WARD, H. REN, B. VALLANAT, M. Devito, AND C. CORTON. Xenobiotic metabolizing enzyme (XME) expression in aging humans. Presented at Society of Toxicology , Baltimore, MD, March 15 - 19, 2009.
Impact/Purpose:
This work addresses the issues of potentially sensitive subpopulations which include the very young and very old. We have characterized the gene expression profiles in the livers of young and old humans and determined there are differences in the expression of xenobiotic metabolizing enzymes that indicacte that older adults are distinct in their ability to metabolize zenobiotics.
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. Our previous microarray studies demonstrate that age alters the expression of XMEs in rats and mice. To determine if aged humans also exhibit changes in XME expression, we examined gene expression profiles using Affymetrix Human U133 Plus 2.0 arrays in liver samples from young (21-45 years) and old (69+ years) men and women. Five to seven livers per age group were profiled. Differentially expressed genes (DEG) were determined using a one-way ANOVA (p≤0.05) by Rosetta Resolver® and a Benjamini-Hochberg FDR multiple testing correction (<0.05). Principal component analysis showed a clear age-dependent separation in expression profiles between young and old hepatic transcripts in males and females. We identified 370 genes that were altered between young and old men and 1163 genes that were altered between young and old women. Top canonical pathways were identified using Ingenuity® Pathway Analysis. Protein ubiquitination pathway is affected in both older men and women. We found that age caused minimal numbers of changes in the gene expression of XMEs (8 in males and 33 in females between young and old, respectively). Most of these changes were in the expression of Phase III genes (transporters). The expression of solute carriers increased with age in men, and the majority decreased with age in women. In addition, we identified 93 or 49 gene expression differences between men and women in the young or old groups, respectively, some of which were XMEs. These studies indicate that the livers from aging humans exhibit a number of changes in XMEs that may lead to differences in the metabolism of xenobiotics.