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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Developmental Expression of Human Hepatic CYP2C9 and CYP2C19

Sevasti B. Koukouritaki, Jason R. Manro, Sandra A. Marsh, Jeffrey C. Stevens, Allan E. Rettie, D. Gail McCarver and Ronald N. Hines
Journal of Pharmacology and Experimental Therapeutics March 2004, 308 (3) 965-974; DOI: https://doi.org/10.1124/jpet.103.060137
Sevasti B. Koukouritaki
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Jason R. Manro
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Sandra A. Marsh
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Jeffrey C. Stevens
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Allan E. Rettie
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D. Gail McCarver
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Ronald N. Hines
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Abstract

The CYP2C subfamily is responsible for metabolizing many important drugs and accounts for about 20% of the cytochrome P450 in adult liver. To determine developmental expression patterns, liver microsomal CYP2C9 and -2C19 were measured (n = 237; ages, 8 weeks gestation-18 years) by Western blotting and with diclofenac or mephenytoin, respectively, as probe substrates. CYP2C9-specific content and catalytic activity were consistent with expression at 1 to 2% of mature values (i.e., specific content, 18.3 pmol/mg protein and n = 79; specific activity, 549.5 pmol/mg/min and n = 72) during the first trimester, with progressive increases during the second and third trimesters to levels approximately 30% of mature values. From birth to 5 months, CYP2C9 protein values varied 35-fold and were significantly higher than those observed during the late fetal period, with 51% of samples exhibiting values commensurate with mature levels. Less variable CYP2C9 protein and activity values were observed between 5 months and 18 years. CYP2C19 protein and catalytic activities that were 12 to 15% of mature values (i.e., specific content, 14.6 pmol/mg and n = 20; specific activity, 18.5 pmol/mg/min and n = 19) were observed as early as 8 weeks of gestation and were similar throughout the prenatal period. CYP2C19 expression did not change at birth, increased linearly over the first 5 postnatal months, and varied 21-fold from 5 months to 10 years. Adult CYP2C19 protein and activity values were observed in samples older than 10 years. The ontogeny of CYP2C9 and -2C19 were dissimilar among both fetal and 0- to 5-months postnatal samples, implying different developmental regulatory mechanisms.

Footnotes

  • These studies were supported in part by funds from the Children's Hospital Foundation of Wisconsin (to R.N.H. and D.G.M.) and National Institutes of Health Grant GM32165 (to A.E.R.).

  • DOI: 10.1124/jpet.103.060137.

  • ABBREVIATIONS: CAR, constitutive androstane receptor; GR, glucocorticoid receptor; HNF, hepatocyte nuclear factor; PXR, pregnane X receptor; ANOVA, analysis of variance.

    • Received September 16, 2003.
    • Accepted November 14, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 308 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 308, Issue 3
1 Mar 2004
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Developmental Expression of Human Hepatic CYP2C9 and CYP2C19

Sevasti B. Koukouritaki, Jason R. Manro, Sandra A. Marsh, Jeffrey C. Stevens, Allan E. Rettie, D. Gail McCarver and Ronald N. Hines
Journal of Pharmacology and Experimental Therapeutics March 1, 2004, 308 (3) 965-974; DOI: https://doi.org/10.1124/jpet.103.060137

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Developmental Expression of Human Hepatic CYP2C9 and CYP2C19

Sevasti B. Koukouritaki, Jason R. Manro, Sandra A. Marsh, Jeffrey C. Stevens, Allan E. Rettie, D. Gail McCarver and Ronald N. Hines
Journal of Pharmacology and Experimental Therapeutics March 1, 2004, 308 (3) 965-974; DOI: https://doi.org/10.1124/jpet.103.060137
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