Cytochrome P450 and Flavin-containing Monooxygenase Families: Age-Dependent Differences in Expression and Functional Activity

BACKGROUND: Age-dependent differences in pharmacokinetics exist for metabolically cleared medications. Differential contributions in the cytochrome P450 3A (CYP3A), CYP2C, and flavin-containing monooxygenases (FMO) families play an important role in the metabolic clearance of a large number of drugs administered to children. METHODS: Unlike previous semi-quantitative characterization of age-dependent changes in the expression of genes and proteins (Western 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, FMO1) to adult isoforms (CYP3A4, FMO3) at birth, while CYP2C9 showed a linear maturation from birth into adulthood. In contrast, analysis of CYP2C19 revealed higher expression and catalytic efficiency in pediatric samples compared to fetal and adult samples. Further, CYP3A and FMO enzymes exhibited an unexpected higher functional activity in fetal samples not entirely explained by protein expression. CONCLUSIONS: These surprising findings suggest that CYP and FMO enzymes may encounter development-related differences in their micro environments that can influence the enzyme activity in addition to protein expression levels.