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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

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

Jill S. Warrington, David J. Greenblatt and Lisa L. von Moltke
Journal of Pharmacology and Experimental Therapeutics May 2004, 309 (2) 720-729; DOI: https://doi.org/10.1124/jpet.103.061077
Jill S. Warrington
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David J. Greenblatt
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Lisa L. von Moltke
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Abstract

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.

Footnotes

  • This work was supported by Grants MH-58435, AG-17880, DA-13209, DK/AI-58496, DA-05258, DA-13834, MH-34223, MH-01237, and RR-00054 from the Department of Health and Human Services. Animals were provided through a Pilot Study/Dissertation Research Program at the National Institute of Aging.

  • DOI: 10.1124/jpet.103.061077.

  • ABBREVIATIONS: P450, cytochrome P450; TRZ, triazolam; OH, hydroxy; PMSF, phenylmethylsulfonyl chloride; HPLC, high-performance liquid chromotography; Vmax, maximal reaction velocity; Km, substrate concentration at 50% Vmax; CLint, intrinsic clearance; TBS, Tris-buffered saline; ANOVA, analysis of variance.

    • Received October 7, 2003.
    • Accepted January 21, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 309 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 309, Issue 2
1 May 2004
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

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

Jill S. Warrington, David J. Greenblatt and Lisa L. von Moltke
Journal of Pharmacology and Experimental Therapeutics May 1, 2004, 309 (2) 720-729; DOI: https://doi.org/10.1124/jpet.103.061077

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

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

Jill S. Warrington, David J. Greenblatt and Lisa L. von Moltke
Journal of Pharmacology and Experimental Therapeutics May 1, 2004, 309 (2) 720-729; DOI: https://doi.org/10.1124/jpet.103.061077
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