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Coordinated Changes in Xenobiotic Metabolizing Enzyme Gene Expression in Aging Male Rats
Citation:
LEE, J. S., W. O. WARD, D. C. WOLF, J. W. ALLEN, C. Mills, M. J. DEVITO, AND C. CORTON. Coordinated Changes in Xenobiotic Metabolizing Enzyme Gene Expression in Aging Male Rats. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 106(1):263-283, (2008).
Impact/Purpose:
Very little is known about the impact of aging on the expression of xenobiotic metabolizing enzymes and the relationships between age-dependent differences in expression and chemical susceptibility between different age groups. In this study changes in XME expression in aging male rat livers were categorized to hypothesize altered responses to environmental chemicals with age.
Description:
In order to gain better insight on aging and susceptibility, we characterized the expression of xenobiotic metabolizing enzymes (XMEs) from the livers of rats to evaluate the change in capacity to respond to xenobiotics across the adult lifespan. Gene expression profiles for XMEs in male F344 and Brown Norway rats 4 to 24 months old were generated using full-genome arrays. In addition, Brown Norway rats were exposed to toluene by oral gavage to examine metabolic processes across the lifespan when challenged with a xenobiotic compound. Principal component analysis showed a clear age-dependent separation between young and old for both rat strains. Out of 1135 or 1435 genes altered between the old and young groups in the F344 and Brown Norway rats respectively, 7% and 3% were XMEs (phase I, II and III classes). Lipid, ergosterol, alcohol, and fatty acid metabolism genes were also altered with age in both strains. Most of the genes altered by age exhibited a gender-dependent expression pattern in young adult rats, suggesting an increasingly feminized pattern of gene expression with age in male rats. Toluene exposure decreased the expression of glutathione synthetase, and the percentage of phase III enzymes being down-regulated increased significantly. The expression of CYP2B2 and glutathione-S-transferase decreased with age but increased in all age groups after toluene exposure. Decreased ability to detoxify and transport chemicals out of the body with age could result in increased susceptibility to some classes of chemicals in the aging population.
What is the study?
Exposures to environmental toxicants in older adults may be similar to those experienced by the general population, but there are a number of pharmacokinetic changes associated with aging that may increase susceptibility in this segment of the population (Geller and Zenick, 2005). This study, which supports the agency's Aging Initiative, examines genomic indicators of changes in hepatic xenobiotic metabolizing enzymes in two strains of aging rats as a step towards defining potential mediators of susceptibility and considering specific environmental compounds targeted by those XMEs.
Why was it done?
Very little is known about the impact of aging on the expression of xenobiotic metabolizing enzymes and the relationships between age-dependent differences in expression and chemical susceptibility between different age groups. In this study changes in XME expression in aging male rat livers were categorized to hypothesize altered responses to environmental chemicals with age.
What is the impact to the field and the agency?
The results of this study suggest an age-related decreased ability to detoxify and transport chemicals out of the body may lead to an increased susceptibility to chemicals in the aging population. This information identifies additional risk factors and provides scientific support for conducting risk assessments that consider the aging as a susceptible subpopulation. Since humans metabolize chemicals in a similar manner, the aging human population may be more susceptible to chemicals because of a decrease in metabolic capacity.
