title: Hepatic transcript levels for genes coding for enzymes associated with xenobiotic metabolism are altered with age.
abstract: 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.
authors: National Institute of Environmental Health Sciences, Research Triangle Park, NC 27701, USA.
authors: Kazuhiko
authors: K
authors: Mori
authors: Pamela E
authors: PE
authors: Blackshear
authors: Edward K
authors: EK
authors: Lobenhofer
authors: Joel S
authors: JS
authors: Parker
authors: Denise P
authors: DP
authors: Orzech
authors: Joseph H
authors: JH
authors: Roycroft
authors: Kimwa L
authors: KL
authors: Walker
authors: Kennita A
authors: KA
authors: Johnson
authors: Tiwanda A
authors: TA
authors: Marsh
authors: Richard D
authors: RD
authors: Irwin
authors: Gary A
authors: GA
authors: Boorman
mesh_terms: D000367:Age Factors; D000375:Aging / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2; D015971:Gene Expression Regulation, Enzymologic; D008099:Liver / Q000201:enzymology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D011916:Rats, Inbred F344; D015203:Reproducibility of Results; D039181:Steroid 16-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism*; D018675:Toxicity Tests; D014158:Transcription, Genetic / Q000502:physiology; D015262:Xenobiotics / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins; D015262:Xenobiotics; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; C465260:Cyp3a2 protein, rat; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase