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Research ArticleArticle

Constitutive and Inducible Hepatic Cytochrome P450 Isoforms in Senescent Male and Female Rats and Response to Low-Dose Phenobarbital

Arun K. Agrawal and Bernard H. Shapiro
Drug Metabolism and Disposition May 2003, 31 (5) 612-619; DOI: https://doi.org/10.1124/dmd.31.5.612
Arun K. Agrawal
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Bernard H. Shapiro
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Abstract

Numerous studies, usually limited to male rodents, have reported an inverse relationship between the age of the animal and the activities of various multi-cytochrome P450-dependent drug-metabolizing enzymes. It has been suggested that the aging-induced decline in hepatic drug-metabolizing capacity is solely a male phenomenon. That is, whereas the levels of male-specific isoforms of P450 decline with senescence, the female-dependent isoforms remain unchanged in females and even increase in male liver. In addition to their baseline activities, induction levels of hepatic monooxygenases have also been reported to decrease with aging. To examine aging- and sex-dependent effects on drug metabolism at a more molecular level, we measured the expression (mRNA, protein, and/or catalytic activity) of a near dozen constitutive and inducible isoforms of P450 in 5-and 23-month-old male and female Sprague-Dawley rats. Moreover, we investigated the induction effects of low concentrations of phenobarbital known to reveal gender differences and the threshold sensitivities of both constitutive and inducible isoforms. With the exception of male-specific CYP2C11 (whose expression declined ∼70% in aged male rats), we observed little senescence-associated reduction in either preinduction or induction levels of CYP2B1, CYP2B2, CYP3A1, CYP3A2, CYP2C6, CYP2C7, CYP2C12, and CYP2C13 in either male or female rats. Moreover, the sexually dimorphic expression levels apparent at 5 months of age persisted in the old rats.

Footnotes

  • ↵1 Current address: Department of Drug Metabolism, Merck Research Laboratories, P.O. Box 2000, RY80E-200, Rahway, NJ 07065-0900.

  • This work was supported by National Institutes of Health Grant HD16358 and GM45758.

  • ↵3 Having distinctly different mobilities, the antibody clearly differentiates CYP2C12 from CYP2C13 (Pampori and Shapiro, 1999).

  • ↵4 Although testosterone 5α-reductase coincidentally reflects the levels of CYP2C12, it is not CYP2C12-dependent (Waxman, 1991). Nevertheless, we observed a 4-fold increase in the activity of the reductase in 23-month-old males reducing the male/female ratio of 1:24 in 5-month-old rats to 1:6 at 23 months of age.

  • ↵5 This uncoupling of transcription from translation may be explained by the induction of an aberrant, untranslatable species of CYP2C11 mRNA characterized by the retention of its terminal intron (Pampori and Shapiro, 2000).

  • Abbreviations used are::
    P450
    cytochrome P450
    • Received August 19, 2002.
    • Accepted February 3, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 31 (5)
Drug Metabolism and Disposition
Vol. 31, Issue 5
1 May 2003
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Research ArticleArticle

Constitutive and Inducible Hepatic Cytochrome P450 Isoforms in Senescent Male and Female Rats and Response to Low-Dose Phenobarbital

Arun K. Agrawal and Bernard H. Shapiro
Drug Metabolism and Disposition May 1, 2003, 31 (5) 612-619; DOI: https://doi.org/10.1124/dmd.31.5.612

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Research ArticleArticle

Constitutive and Inducible Hepatic Cytochrome P450 Isoforms in Senescent Male and Female Rats and Response to Low-Dose Phenobarbital

Arun K. Agrawal and Bernard H. Shapiro
Drug Metabolism and Disposition May 1, 2003, 31 (5) 612-619; DOI: https://doi.org/10.1124/dmd.31.5.612
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