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Developmental expression of human hepatic CYP2C9 and CYP2C19
Sevasti B Koukouritaki1, Jason R Manro, Sandra A Marsh
1Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226-4801, USA.
The Journal of Pharmacology and Experimental Therapeutics
|November 25, 2003
Summary
Drug-metabolizing CYP2C9 and CYP2C19 enzymes show distinct developmental patterns in the liver. CYP2C9 levels rise significantly after birth, while CYP2C19 matures earlier in gestation, indicating different regulatory mechanisms.
Area of Science:
- Pharmacology
- Biochemistry
- Developmental Biology
Background:
- The CYP2C subfamily is crucial for drug metabolism, representing approximately 20% of adult liver cytochrome P450.
- Understanding the developmental expression of CYP2C enzymes is vital for pediatric drug therapy.
Purpose of the Study:
- To investigate the developmental expression patterns of CYP2C9 and CYP2C19 in the human liver.
- To compare the ontogeny of CYP2C9 and CYP2C19 and identify potential differences in their regulatory mechanisms.
Main Methods:
- Liver microsomes from 237 individuals (8 weeks gestation to 18 years) were analyzed.
- CYP2C9 and CYP2C19 protein levels and catalytic activities were measured using Western blotting and specific probe substrates (diclofenac and mephenytoin, respectively).
Main Results:
- CYP2C9 expression was low in early gestation (1-2% of mature levels), increasing to ~30% by the third trimester, and significantly rising post-birth to mature levels in 51% of infants by 5 months.
- CYP2C19 expression was detected early (8 weeks gestation) at 12-15% of mature levels, remaining stable prenatally, then increasing linearly in the first 5 postnatal months, reaching adult levels after 10 years.
- The developmental trajectories of CYP2C9 and CYP2C19 differed significantly in fetal and early postnatal stages.
Conclusions:
- CYP2C9 and CYP2C19 exhibit distinct ontogeny, suggesting different developmental regulation.
- These findings highlight the importance of considering developmental stage in pediatric drug metabolism and dosing.