Age-Related Differences in CYP3A Expression and Activity in the Rat Liver, Intestine, and Kidney

We evaluated the effect of age on CYP3A expression and function in the liver, intestine, and kidney from young (3-4 months), intermediate (13-14 months), and old (25-26 months) male Fischer-344 rats. The biotransformation of triazolam to its primary hydroxylated products, 4-OH-TRZ (triazolam) and α...

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Bibliographic Details
Published in:The Journal of pharmacology and experimental therapeutics 2004-05, Vol.309 (2), p.720-729
Main Authors: Warrington, Jill S, Greenblatt, David J, von Moltke, Lisa L
Format: Article
Language:English
Subjects:
Age Factors
Aging - metabolism
Animals
Antibodies - pharmacology
Aryl Hydrocarbon Hydroxylases - metabolism
Blotting, Western
Cytochrome P-450 CYP3A
Gene Expression - physiology
Hydroxylation
Intestines - enzymology
Kidney - enzymology
Liver - enzymology
Male
Oxidoreductases, N-Demethylating - metabolism
Rats
Rats, Inbred F344
Testosterone - blood
Triazolam - metabolism
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Summary:We evaluated the effect of age on CYP3A expression and function in the liver, intestine, and kidney from young (3-4 months), intermediate (13-14 months), and old (25-26 months) male Fischer-344 rats. The biotransformation of triazolam to its primary hydroxylated products, 4-OH-TRZ (triazolam) and α-OH-TRZ, was used as a marker of CYP3A activity in rat liver and intestine. Immunoactive CYP3A expression was evaluated by Western blot analysis in the rat intestine, liver, and kidney. Since testosterone and NADPH reductase levels may modulate CYP3A activity, we also examined free plasma testosterone concentrations and NADPH reductase expression in these rats. The effect of age on CYP3A expression was tissue-specific. Although both CYP3A activity and expression were reduced by approximately 50 to 70% in the old livers compared with the young animals, intestinal CYP3A activity and expression did not change significantly with age. The expression of one CYP3A isoform was increased by 1.5-fold in the old kidneys. NADPH reductase expression was reduced by 23 to 36% with age in all tissues; this reached statistical significance only in the liver. Plasma testosterone levels declined by 74% in the old animals. This study suggests that the effect of age on CYP3A expression and function is tissue-specific. In addition, changes in testosterone levels and NADPH reductase expression may contribute to age-related differences in hepatic CYP3A activity.
ISSN:0022-3565
1521-0103
DOI:10.1124/jpet.103.061077