Toxicologic Pathology

 

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Toxicologic Pathology, Vol. 35, No. 2, 242-251 (2007)
DOI: 10.1080/01926230601156286

Articles

Hepatic Transcript Levels for Genes Coding for Enzymes Associated with Xenobiotic Metabolism are Altered with Age

Kazuhiko Mori1, Pamela E. Blackshear2, Edward K. Lobenhofer3, Joel S. Parker4, Denise P. Orzech1, Joseph H. Roycroft1, Kimwa L. Walker2, Kennita A. Johnson1, Tiwanda A. Marsh1, Richard D. Irwin1 and Gary A. Boorman1

1 National Institute of Environmental Health Sciences, Research Triangle Park, NC 27701, USA
2 Integrated Laboratory Systems, Inc., Research Triangle Park, NC 27709 USA
3 Cogenics, a Division of A Clinical Data, Morrisville, NC 27564, USA
4 Constella Group, Inc., Research Triangle Park, NC 27709, USA

Correspondence: Address correspondence to: Gary A. Boorman, The National Institute of Environmental Heath Sciences, MD B3-08, Environmental Toxicology Program, P.O. Box 12233, 111 T. W. Alexander Drive, Research Triangle Park, NC 27709; e-mail:boorman{at}niehs.nih.gov

Metabolism studies are crucial for data interpretation from rodent toxicity and carcinogenicity studies. Metabolism studies are usually conducted in 6 to 8 week old rodents. Long-term studies often continue beyond 100 weeks of age. The potential for age-related changes in transcript levels of genes encoding for enzymes associated with metabolism was evaluated in the liver of male F344/N rats at 32, 58, and 84 weeks of age. Differential expression was found between the young and old rats for genes whose products are involved in both phase I and phase II metabolic pathways. Thirteen cytochrome P450 genes from CYP families 1–3 showed alterations in expression in the older rats. A marked age-related decrease in expression was found for 4 members of the Cyp3a family that are critical for drug metabolism in the rat. Immunohistochemical results confirmed a significant decrease in Cyp3a2 and Cyp2c11 protein levels with age. This indicates that the metabolic capacity of male rats changes throughout a long-term study. Conducting multiple hepatic microarray analyses during the conduct of a long-term study can provide a global view of potential metabolic changes that might occur. Alterations that are considered crucial to the interpretation of long-term study results could then be confirmed by subsequent metabolic studies.

Key Words: Liver • rat • transcriptome • aging • cytochrome P450 • xenobiotic metabolism

Abbreviations: RT-PCR, reverse transcription polymerase chain reaction • SAM, Statistical analysis of microarray • NTP, National Toxicology Program • CYP, cytochrome P450 family of enzymes


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