RT Journal Article
SR Electronic
T1 Developmental Expression of Human Hepatic CYP2C9 and CYP2C19
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 965
OP 974
DO 10.1124/jpet.103.060137
VO 308
IS 3
A1 Koukouritaki, Sevasti B.
A1 Manro, Jason R.
A1 Marsh, Sandra A.
A1 Stevens, Jeffrey C.
A1 Rettie, Allan E.
A1 McCarver, D. Gail
A1 Hines, Ronald N.
YR 2004
UL http://jpet.aspetjournals.org/content/308/3/965.abstract
AB 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. The American Society for Pharmacology and Experimental Therapeutics