Developmental changes in human liver CYP2D6 expression.
Within the human cytochrome P450 family, specific forms show developmental expression patterns that can affect drug clearance, efficacy, and safety. The objective of this study was to use dextromethorphan O-demethylase activity and quantitative Western blotting to identify CYP2D6 developmental expression patterns in a large (n = 222) and developmentally diverse set of pediatric liver samples. Immunodetectable levels of CYP2D6 protein determined for selected samples across all age categories showed a significant correlation with the corresponding dextromethorphan O-demethylase activity. Of gender, ethnicity, postmortem interval, and genotype, only increasing gestational age was associated with CYP2D6 activity and protein content in prenatal samples. In contrast, both age and genotype were associated with CYP2D6 expression in postnatal samples. CYP2D6 expression in liver samples from neonates less than 7 days of age was higher than that observed in first and second trimester samples, but not significantly higher than third trimester fetal samples. In contrast, expression in postnatal samples greater than 7 days of age was substantially higher than that for any earlier age category. Higher CYP2D6 expression also was observed in liver samples from Caucasians versus African Americans. Finally, using phenotype categories inferred from genotype, CYP2D6 activity was higher in postnatal samples predicted to be extensive or intermediate metabolizers versus poor metabolizers. These results suggest that age and genetic determinants of CYP2D6 expression constitute significant determinants of interindividual variability in CYP2D6-dependent metabolism during ontogeny.
Stevens
Jeffrey C
JC
Pfizer Corporation, Global Research and Development, Chesterfield, Missouri, USA.
Marsh
Sandra A
SA
Zaya
Matthew J
MJ
Regina
Karen J
KJ
Divakaran
Karthika
K
Le
Min
M
Hines
Ronald N
RN
D015153:Blotting, Western; D002648:Child; D002675:Child, Preschool; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology
D019389:Cytochrome P-450 CYP2D6