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BUILDING REALISTIC BIOLOGICALLY-BASED PHARMACOKINETIC MODELS FOR PREDICTING SUSCEPTIBILITY IN THE AGED POPULATIONS
Citation:
LEE, J. S., D. C. WOLF, J. W. ALLEN, W. O. WARD, R. TORNERO-VELEZ, M. J. DEVITO, AND C. CORTON. BUILDING REALISTIC BIOLOGICALLY-BASED PHARMACOKINETIC MODELS FOR PREDICTING SUSCEPTIBILITY IN THE AGED POPULATIONS. Presented at International Science Forum on Computational Toxicology, RTP, NC, May 21 - 23, 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 Fischer rats and male Brown Norway rats. Gene expression profiles for XMEs in male Fischer rats (6, 11, 18, 24 months of age) and male Brown Norway rats (4, 12, 24 months of age) were generated using Affymetrix Rat 230 2.0 arrays. Four animals per age group were profiled for the Fischer rats, and three animals per age group were profiled for the Brown Norway rats. Principal component analysis showed a clear age-dependent separation in expression profiles between young and old hepatic transcripts for both rat strains. Differentially expressed genes (DEG) 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 Cyber T statistics. For the Fischer rats, 1135 genes were found to be significantly altered in a 24 versus 6 month comparison, and 155 genes were significantly altered in an 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 18 versus 6 month comparison, we found 3 phase I and 2 phase III metabolism genes significantly altered. For the Brown Norway rats, 1632 genes were found to be significantly altered in a 24 versus 4 month comparison, and 1130 genes were significantly altered in a 12 versus 4 month comparison. In the 24 versus 4 month comparison, we found 21 phase I, 9 phase II, and 34 phase III metabolism genes significantly altered. In the 12 versus 4 month comparison, we found 6 phase I, 1 phase II, and 16 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 Fischer and Brown Norway rats. Results were also compared to existing aging mouse and human datasets. Alternative splicing in young and old male SV129 mice is also being examined using Affymetrix mouse exon arrays. Gene expression data, along with enzyme activity data, will be used to improve pharmacokinetic models of the aged by incorporating transcript profile information on the differences in xenobiotic metabolism gene expression between young and old populations.