Developmental expression of CYP2C and CYP2C-dependent activities in the human liver: in-vivo/in-vitro correlation and inducibility.

Experiments were performed in vivo and in vitro to date the onset of hepatic CYP2C isoforms and CYP2C-dependent activities during the perinatal period in humans. Proteins were not detected by immunoblotting in fetal livers and developed in the first few weeks after birth, irrespective of the gestational age at birth. Similarly, the hydroxylation of tolbutamide, a marker for CYP2C9 was undetected in fetal liver microsomes and rose in the first month after birth. In adult liver preparations, the hydroxylation of diazepam correlated well with the CYP3 A content of microsomes (r = 0.858, p < 0.01) and with the 6 beta hydroxylation of testosterone (r = 0.830, p < 0.005), whereas demethylation was related to the bulk of CYP2C proteins (r = 0.865, p < 0.005). In fetal liver microsomes, hydroxylation and demethylation activities accounted for less than 5% of the adult activities and both increased immediately after birth to reach adult activities at 1 year of age. When diazepam was given for sedative purpose in neonates and infants, the in-vivo urinary excretion of desmethyl diazepam, temazepam and oxazepam was extremely low in 1-2 day newborns (less than 5 nmol metabolites excreted in 24 h per kg body weight) and developed in the first week after birth. In newborns, barbiturates and to a lesser extent steroids, acted as inducers of CYP2C isoforms and increased tolbutamide hydroxylation, diazepam demethylation and diazepam hydroxylation by 2 to 10-fold. The surge of CYP2C proteins was caused by an accumulation of RNAs occurring in the first week after birth. The hepatic content in CYP2C8, 2C9 and 2C18 RNA displayed the same profile of evolution, which suggested a coregulation of their synthesis during the neonatal period. Taken together, these biochemical and clinical data enable dating of the onset of CYP2C proteins to the first weeks after birth, which is of considerable clinical importance in pediatric pharmacology.