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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Developmental Expression of the Major Human Hepatic CYP3A Enzymes

Jeffrey C. Stevens, Ronald N. Hines, Chungang Gu, Sevasti B. Koukouritaki, Jason R. Manro, Peter J. Tandler and Matthew J. Zaya
Journal of Pharmacology and Experimental Therapeutics November 2003, 307 (2) 573-582; DOI: https://doi.org/10.1124/jpet.103.054841
Jeffrey C. Stevens
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Ronald N. Hines
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Chungang Gu
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Sevasti B. Koukouritaki
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Jason R. Manro
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Peter J. Tandler
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Matthew J. Zaya
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Abstract

The human cytochrome P4503A forms show expression patterns subject to developmental influence. CYP3A7 and CYP3A4 are generally classified as the major fetal and adult liver forms, respectively. However, characterization of CYP3A4, -3A5, and -3A7 developmental expression has historically been confounded by the lack of CYP3A isoform-specific antibodies or marker enzyme activities. Therefore, the objective of this study was to characterize the developmental expression of hepatic CYP3A forms from early gestation to 18 years of age using up to 212 fetal and pediatric liver samples. Based on immunoquantitation, CYP3A5 protein expression was found to be highly variable, generally independent of age, and more frequently observed for African-American individuals. For differentiation of CYP3A4 and -3A7 levels, dehydroepiandrosterone metabolite patterns for expressed CYP3A forms were characterized and used for simultaneous quantitation of protein levels within liver microsome samples. The major metabolite formed by CYP3A4, 7β-hydroxy-dehydroepiandrosterone, was identified based on cochromatography and mass spectra matching with the authentic standard. Kinetic analysis showed a 34-fold greater intrinsic clearance of 7β-hydroxy-dehydroepiandrosterone by CYP3A4 versus -3A7, whereas CYP3A7 showed the highest 16α-hydroxy-dehydroepiandrosterone intrinsic clearance. Metabolite profiles for the expressed enzymes were fit to a multiple response model and CYP3A4 and -3A7 levels in fetal and pediatric liver microsome samples were calculated. Fetal liver microsomes showed extremely high CYP3A7 levels (311-158 pmol/mg protein) and significant expression through 6 months postnatal age. Low CYP3A4 expression was noted for fetal liver (≤10 pmol/mg), with mean levels increasing with postnatal age.

Footnotes

  • This study was supported in part by National Institutes of Health Grant CA53106 (to R.N.H.) and previously presented in part at the 11th North American Meeting of the International Society for the Study of Xenobiotics, Orlando, FL, October 2002.

  • DOI: 10.1124/jpet.103.054841.

  • ABBREVIATIONS: P450, cytochrome P450; PMI, post-mortem interval; DHEA, dehydroepiandrosterone; LC-MS, liquid chromatography-mass spectrometry; APCI, atmosphere pressure chemical ionization; Clint, intrinsic clearance; EGA, estimated gestational age; PNA, postnatal age.

    • Received May 22, 2003.
    • Accepted August 6, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 307 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 307, Issue 2
1 Nov 2003
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Developmental Expression of the Major Human Hepatic CYP3A Enzymes

Jeffrey C. Stevens, Ronald N. Hines, Chungang Gu, Sevasti B. Koukouritaki, Jason R. Manro, Peter J. Tandler and Matthew J. Zaya
Journal of Pharmacology and Experimental Therapeutics November 1, 2003, 307 (2) 573-582; DOI: https://doi.org/10.1124/jpet.103.054841

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Developmental Expression of the Major Human Hepatic CYP3A Enzymes

Jeffrey C. Stevens, Ronald N. Hines, Chungang Gu, Sevasti B. Koukouritaki, Jason R. Manro, Peter J. Tandler and Matthew J. Zaya
Journal of Pharmacology and Experimental Therapeutics November 1, 2003, 307 (2) 573-582; DOI: https://doi.org/10.1124/jpet.103.054841
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