Cytochrome P450 and flavin-containing monooxygenase families: Age-dependent differences in expression and functional activity

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Issue Date
2017-11-01Author
Zane, Nicole R.
Chen, Yao
Wang, Michael Zhuo
Thakker, Dhiren R.
Publisher
Springer Nature
Type
Article
Article Version
Scholarly/refereed, author accepted manuscript
Rights
Copyright © 2018 International Pediatric Research Foundation, Inc.
Metadata
Show full item recordAbstract
Background
Age-dependent differences in pharmacokinetics exist for metabolically cleared medications. Differential contributions in the cytochrome P450 3A (CYP3A), CYP2C, and flavin-containing monooxygenases (FMOs) families have an important role in the metabolic clearance of a large number of drugs administered to children.Methods
Unlike previous semiquantitative characterization of age-dependent changes in the expression of genes and proteins (western blot analysis), this study quantifies both gene and absolute protein expression in the same fetal, pediatric, and adult hepatic tissue. Expression was then correlated with the corresponding functional activities in the same samples.Results
CYP3A and FMO families showed a distinct switch from fetal (CYP3A7 and FMO1) to adult isoforms (CYP3A4 and FMO3) at birth, whereas CYP2C9 showed a linear maturation from birth into adulthood. In contrast, analysis of CYP2C19 revealed higher expression and catalytic efficiency in pediatric samples compared with that in fetal and adult samples. Further, CYP3A and FMO enzymes exhibited an unexpectedly higher functional activity in fetal samples not entirely explained by protein expression.Conclusion
These surprising findings suggest that CYP and FMO enzymes may encounter development-related differences in their microenvironments that can influence the enzyme activity in addition to protein expression levels.
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Citation
Zane, N. R., Chen, Y., Wang, M. Z., & Thakker, D. R. (2018). Cytochrome P450 and flavin-containing monooxygenase families: age-dependent differences in expression and functional activity. Pediatric research, 83(2), 527–535. https://doi.org/10.1038/pr.2017.226
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