Ontogeny of human hepatic cytochromes P450

Significant changes in drug‐metabolizing enzyme (DME) expression occur during ontogeny. Such changes can have a profound effect on therapeutic efficacy in the fetus and child, as well as the risk for adverse drug reactions. To gain a better understanding of DME ontogeny, enzyme contents for six key...

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Bibliographic Details
Published in:Journal of Biochemical and Molecular Toxicology 2007-08, Vol.21 (4), p.169-175
Main Author: Hines, Ronald N.
Format: Article
Language:English
Subjects:
Adolescent
Age Factors
Aryl Hydrocarbon Hydroxylases - analysis
Aryl Hydrocarbon Hydroxylases - metabolism
Child
Child, Preschool
CYP2C19
CYP2C9
CYP2E1
CYP3A4
CYP3A5
CYP3A7
Cytochrome P-450 CYP2C19
Cytochrome P-450 CYP2C9
Cytochrome P-450 CYP2E1 - analysis
Cytochrome P-450 CYP3A
Cytochrome P-450 Enzyme System - analysis
Cytochrome P-450 Enzyme System - chemistry
Cytochrome P-450 Enzyme System - metabolism
Cytochrome P450
Developmental Pharmacology
Gene Expression Regulation, Developmental
Gene Expression Regulation, Enzymologic
Humans
Infant
Liver - enzymology
Liver - growth & development
Mixed Function Oxygenases - analysis
Mixed Function Oxygenases - metabolism
Ontogeny
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Summary:Significant changes in drug‐metabolizing enzyme (DME) expression occur during ontogeny. Such changes can have a profound effect on therapeutic efficacy in the fetus and child, as well as the risk for adverse drug reactions. To gain a better understanding of DME ontogeny, enzyme contents for six key cytochromes P450 were measured in 240 human liver samples representing ages from 8 weeks gestation to 18 years. Where possible, both quantitative western blotting and activity assays with probe substrates were performed. Although oversimplified, the DME can be grouped into one of three categories. As typified by CYP3A7, some enzymes are expressed at their highest level during the first trimester and either remain at high concentrations or decrease during gestation and are silenced or expressed at low levels within 1–2 years after birth. These data cause one to query whether these enzymes have an important endogenous function. Representatives of a second group, CYP3A5 and CYP2C19, are expressed at relatively constant levels throughout gestation. Postnatal increases in CYP2C19 are observed within the first year, but not for CYP3A5. CYP2C9, 2E1, and 3A4 are more typical of a third group of enzymes that are not expressed or are expressed at low levels in the fetus with the onset of expression generally in either the second or third trimester. Substantial increases in expression are observed within the first 1–2 years after birth; however, considerable interindividual variability is observed in the immediate postnatal (1–6 months) onset or increase in expression of these enzymes, often resulting in a window of hypervariability. © 2007 Wiley Periodicals, Inc. J Biochem Mol Toxicol 21:169–175, 2007; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20179
ISSN:1095-6670
1099-0461
DOI:10.1002/jbt.20179