Developmental expression of human hepatic CYP2C9 and CYP2C19. J Pharmacol Exp Ther 2004 Mar;308(3):965-74
Date
11/25/2003Pubmed ID
14634042DOI
10.1124/jpet.103.060137Scopus ID
2-s2.0-1342344547 (requires institutional sign-in at Scopus site) 293 CitationsAbstract
The CYP2C subfamily is responsible for metabolizing many important drugs and accounts for about 20% of the cytochrome p450 in adult liver. To determine developmental expression patterns, liver microsomal CYP2C9 and -2C19 were measured (n = 237; ages, 8 weeks gestation-18 years) by Western blotting and with diclofenac or mephenytoin, respectively, as probe substrates. CYP2C9-specific content and catalytic activity were consistent with expression at 1 to 2% of mature values (i.e., specific content, 18.3 pmol/mg protein and n = 79; specific activity, 549.5 pmol/mg/min and n = 72) during the first trimester, with progressive increases during the second and third trimesters to levels approximately 30% of mature values. From birth to 5 months, CYP2C9 protein values varied 35-fold and were significantly higher than those observed during the late fetal period, with 51% of samples exhibiting values commensurate with mature levels. Less variable CYP2C9 protein and activity values were observed between 5 months and 18 years. CYP2C19 protein and catalytic activities that were 12 to 15% of mature values (i.e., specific content, 14.6 pmol/mg and n = 20; specific activity, 18.5 pmol/mg/min and n = 19) were observed as early as 8 weeks of gestation and were similar throughout the prenatal period. CYP2C19 expression did not change at birth, increased linearly over the first 5 postnatal months, and varied 21-fold from 5 months to 10 years. Adult CYP2C19 protein and activity values were observed in samples older than 10 years. The ontogeny of CYP2C9 and -2C19 were dissimilar among both fetal and 0- to 5-months postnatal samples, implying different developmental regulatory mechanisms.
Author List
Koukouritaki SB, Manro JR, Marsh SA, Stevens JC, Rettie AE, McCarver DG, Hines RNAuthor
Sevasti Koukouritaki Research Scientist II in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Aryl Hydrocarbon HydroxylasesCytochrome P-450 CYP2C19
Cytochrome P-450 CYP2C9
Gene Expression Regulation, Developmental
Gene Expression Regulation, Enzymologic
Humans
Liver
Mixed Function Oxygenases
